Anti-atherosclerotic diaryl compounds

ABSTRACT

The present invention is concerned with diaryl compounds of formula (l) and their use in medical therapy, particularly in the prophylaxis or treatment of a clinical condition for which an ACAT inhibitor is indicated, such as hyperlipidaema or atherosclerosis. The invention also relates to pharmaceutical compositions and processes for the preparation of compounds according to the invention. ##STR1##

This application is a 371 of PCT/GB94/01409 filed Jun. 29, 1994.

The present invention is concerned with diaryl compounds, processes fortheir preparation, compositions containing them and their use inmedicine, particularly in the prophylaxis and treatment ofatherosclerosis.

The deposition of cholesterol and cholesteryl esters in atheroscleroticlesions is one of the principal pathological processes of atherogenesis.The enzyme acyl coenzyme A: cholesterol acyltransferase (ACAT) catalysesthe synthesis of cholesteryl esters and is thought to play an importantrole in the regulation of intracellular cholesterol metabolism.Inhibition of ACAT is therefore expected to reduce the content ofcholesteryl esters within the lesion and to render the lesion lesscapable of provoking a thrombotic event. To achieve inhibition of lesionACAT, a suitable compound would clearly need to be systemicallybioavailable.

ACAT may also play a key role in the gastrointestinal absorption ofcholesterol on the basis that (a) more than 90% of the cholesterol whichappears in the lymph is esterified, (b) substantial ACAT activity hasbeen observed in the intestinal mucosal cells of several animal species,(c) the site of greatest intestinal ACAT activity is the jejunum wherethe majority of cholesterol absorption occurs, (d) ACAT activity in thejejunum parallels increases in dietary cholesterol. A likely consequenceof inhibiting cholesterol absorption in the gut will be a reduction inplasma cholesterol concentration. There is also evidence that asystemically-available ACAT inhibitor may lower plasma cholesterol byreducing the secretion of very low density lipoprotein by the liver.ACAT inhibitors are known to decrease the absorption of cholesterol fromthe gut and to lower the concentration of total plasma cholesterol in arange of animal models.

European Patent Specification 0370740 discloses diaryl compounds havingnon-systemic ACAT inhibitory activity.

A further class of aryl compounds has now been discovered which arebioavailable and exhibit ACAT inhibitory activity as demonstratedhereinafter in the ACAT inhibition assay in which representativecompounds of the present invention have been shown to be active. Thecompounds of the invention may therefore be particularly useful fordecreasing the steady state concentration of cholesterol and cholesterolester in the arterial wall, thereby retarding and/or reversing thebuild-up of atherosclerotic lesions as well as being hypolipidaemic.

According to the present invention, therefore, there are providedcompounds of formula (I) ##STR2## wherein: W is hydrogen, or a C₁₋₁₂hydrocarbyl group optionally substituted by one or more groupsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, C₁₋₄haloalkyl C₁₋₄ haloalkoxy, and RC(O)-- (wherein R is selected fromhydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy);

X is --NR¹ C(O)NR² --, --NR¹ C(O)O--, --NR¹ C(O)O--, --C(O)NR² --, or--OC(O)NR² -- (wherein R¹ and R² are independently selected fromhydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl);

Y is a bond, C₂₋₄ alkynylene, C₂₋₄ alkenylene (cis or trans), C₁₋₄alkylene, --(CH₂)_(n) --O--(CH₂)_(p) --, or --(CH₂)_(n) --S(O)_(q)--(CH₂)_(p) --, (wherein n and p are integers independently selectedfrom 0, 1, 2, 3, and 4; providing that n+p is not greater than 4; and qis an integer selected from 0, 1, and 2),

and Y is optionally substituted by one or more groups independentlyselected from halo, C₁₋₄ alkyl, and C₁₋₄ haloalkyl;

E is a bond, C₁₋₄ alkylene, --(CH₂)_(r) --)--(CH₂)_(s) --, --(CH₂)_(r)--S(O)_(t) --(CH₂)_(s) --, --(CH₂)_(r) --C(O)--(CH₂)_(s) -- (wherein rand s are integers independently selected from 0, 1, 2, 3 and 4;providing that r+s is not greater than 4; and t is an integer selectedfrom 0, 1, and 2), --OC(O)--, --C(O)O--, --S(O)₂ N(R³)--, --(R³)NS(O)₂--, --C(O)N(R³)--, --(R³)NC(O)N(R⁴)--, or --(R³)NC(O)-- (wherein R³ andR⁴ are independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₄haloalkyl);

Z is an aliphatic ring system, C₁₋₈ alkyl, C₁₋₈ alkoxy, hydroxy, halo,or aryl,

and Z is optionally substituted by one or more groups independentlyselected from halo, cyano, --CO₂ R⁶, --C(O)NR⁶ R⁷, --NR⁶ R⁷ (wherein R⁶and R⁷ are independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₄haloalkyl), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,hydroxy, and C₂₋₈ polyether.

phenyl rings A and B are optionally substituted by one or more groupsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, hydroxy, cyano, R⁸ R⁹ NC(O)--, R⁸ C(O)N(R⁹)--,R⁸ C(O)O--, and R⁸ C(O)-- (wherein R⁸ and R⁹ are independently selectedfrom hydrogen, C₁₋₄ alkyl and C₁₋₄ haloalkyl);

provided that if Y is methylene, ethylene, or n-propylene, or --CH═CH--(cis or trans), then group --E--Z is not C₁₋₆ alkyl optionallysubstituted by one or more independently selected polar groups;

or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof for use in medical therapy; particularly,for use in the prophylaxis or treatment of a clinical condition in amammal, such as a human, for which an ACAT inhibitor is indicated, suchas hyperlipidaemia or atheroclerosis.

In the alternative, the present invention provides a method for theprophylaxis or treatment of a clinical condition in a mammal, such as ahuman, for which an ACAT inhibitor is indicated, such as hyperlipidaemiaor atherosclerosis, which comprises the administration to the mammal ofa therapeutically effective amount of a compound of formula (I) (asdefined above), or a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof

The term "halo" means fluoro, chloro, bromo, or iodo.

The terms "alkyl", "alkoxy", "alkylene", "alkenyl", "alkenylene","alkynyl",and "alkynylene" have meaning as understood by the personskilled in the art and include straight and branched chains.

The terms "haloalkyl" and "haloalkoxy" mean respectively an alkyl oralkoxy group as defined above in which one or more of the hydrogen atomsis replaced by a halo group as defined above, and preferably containingone, two or three halo groups selected from fluoro and chloro. Examplesof such groups include chloromethyl, trifluoromethyl, chloromethoxy andtrifluoromethoxy.

The term "C₁₋₂ hydrocarbyl group" means a straight or branchedhydrocarbon chain of from 1 to 12 carbon atoms which may contain 1 to 4double and/or triple bonds, or a C₃₋₈ saturated or unsaturated cyclichydrocarbon which may contain 1 to 4 double and/or triple bonds.Examples include C₁₋₂ alkenyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkenyl C₈ cycloalkynyl, and C₇₋₁₀ aralkyl.

In the definition of Z the term "aryl" means a monovalent aromaticradical derived from a single ring or 2 fused rings of carbon atoms and,optionally 1 to 4 heteroatoms selected from nitrogen, sulphur, andoxygen. Preferably, in the definition of Z, aryl means carbocyclic arylsuch as phenyl, and 1-, or 2-naphthyl.

The term "aliphatic ring system" means a non-aromatic system of 1 or 2rings containing a total of 3 to 10 carbon atoms, which may contain 1 or2 double and/or triple bonds and optionally one, two or three groupsselected from --N(R⁵)-- (wherein R⁵ is selected from hydrogen, C₁₋₄alkyl, and C₁₋₄ haloalkyl), --C(O)--, --O--, --S--, --S(O)--, and--S(O)₂ --. Suitable examples include C₄₋₇ cycloalkyl, (for example,cyclopentyl or cyclohexyl), or an oxetane, tetrahydrofuran,tetrahydropyran, 1, 3--, or 1, 4-dioxane, 1, 3--, or 1, 4-dioxin,morpholine, 2-oxo-pyrrolidine, 2, 6-dioxo-piperidine,tetrahydrothiopyran, 8-oxabicyclo 3.2.1!octane, 8oxa-3-azabicyclo3.2.1!octane, or 3-oxo-8-azabicyclo 3.2.1!octane group. Preferably, thealiphatic ring system is a single 5-or 6-membered ring.

The term "C₂₋₈ polyether" means a C₂₋₈ alkyl group in which one to fournon-adjacent --CH₂ --groups has been replaced by--O--.

The present invention also provides compounds of formula (I) as definedabove and salts, solvates, and physiologically functional derivativesthereof, with the provisoes that:

(i) when Y is --S--, X is --NR¹ C(O)-- (wherein R¹ is hydrogen or C₁₋₃alkyl), and W is hydrogen or C₁₋₃ alkyl, then--E--Z is not methoxy;

(ii) when Y is --S--or --O--, X is --C(O)NH--, W is hydrogen, ring A isunsubstituted or has one substituent selected from C₁₋₄ alkyl or C₁₋₄alkoxy, and ring B is unsubstituted or has one to three substituentsselected from halogen and alkyl, then--E--Z is not optionallysubstituted cycloalkyl, halogen, or alkylmercapto;

(iii) the compound of formula (I) is not:

N,N-diethyl-2- 2-(4-methoxyphenyl)ethenyl!benzamide,

Bis 2-(N-isopropylcarbamoyl)phenyl!sulphide,

Bis 2-(N-isopropylcarbamoyl)phenyl!sulphoxide,

Bis 2-(N-isopropylcarbamoyl)phenyl!sulphone,

2,2'-thiobis N,N-bis(1-methylpropyl)benzamide!, or

2,2'-thiobis(N-butylbenzamide).

Preferred examples of W include optionally substituted C₃₋₇ alkyl suchas, iso-propyl, tert-butyl, n-heptyl, hydroxycarbonylethyl andethoxycarbonylethyl; more preferably W is C₃₋₅ alkyl; most preferably, Wis tert-butyl.

Preferred examples of X include --C(O)NR² --, --NR¹ C(O)--, and --NR¹C(O)NR² -- (wherein R¹ and R² are as defined for formula (I) and are,for example independently selected from hydrogen and methyl); mostpreferably, X is --C(O)NH--.

Preferred examples of Y include ethylene, ethenylene, ethenylene, --O--,--S--, --CH₂ O--, and --OCH₂ --; more preferably, Y is ethylene,ethenylene, ethenylene, or --O--; most preferably, Y is ethenylene or--O--.

Suitably E is is a bond, C₁₋₄ alkylene, --(CH₂)_(r) --O--(CH₂)_(s),--(CH₂)_(r) --S(O)_(t) --(CH₂)_(s) --, --(CH₂)_(r) --C(O)--(CH₂)_(s) --(wherein r and s are integers independently selected from 0, 1, 2, 3 and4; providing that r+s is not greater than 4; and t is an integerselected from 0, 1, and 2), --S(O)₂ N(R³)--, --(R³)NS(O)₂ --,--C(O)N(R³)--, --(R³)NC(O)N(R⁴)--, or --(R³)NC(O)-- (wherein R³ and R⁴are independently selected from hydrogen, dC₁₋₄ alkyl, C₁₋₄ haloalkyl).Preferred examples of E include --O--, --OCH₂ --, --CH₂ O--, a bond,--C(O)N(R³)--, --(R³)NC(O)--, --S--, --S(O)--, --S(O)₂ --, --(R³)NS(O)₂--, --S(O)₂ N(R³)--, --(R³)NC(O)N(R⁴)--, and--C(O)-- (wherein R³ and R⁴are as defined for formula (I), and are for example, hydrogen); mostpreferably, E is --O--, or a bond.

Suitably, Z is an aliphatic ring system, C₁₋₈ alkyl, C₁₋₈ alkoxy,hydroxy, or aryl and is optionally substituted as described above.Preferably, Z is is a 5-or 6-membered saturated ring optionallycontaining one, two, or three groups selected from --N(R⁵)--(wherein R⁵is selected from hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl), --C(O)--,and --O--, or is C₁₋₄ alkyl C₁₋₄ alkoxy, hydroxy, or aryl and isoptionally substituted as described above. Most preferably, Z is a 5-or6-membered saturated ring optionally containing one, two, or threegroups selected from --N(R⁵)-- (wherein R⁵ is selected from hydrogen,C₁₋₄ alkyl, and C₁₋₄ haloalkyl), --C(O)--, and --O--, or is C₁₋₄ alkyl,or C₁₋₄ alkoxy and is optionally substituted as described above.

Suitably, the substituents on Z are selected from halo, --NR⁶ R⁷(wherein R⁶ and R⁷ are independently selected from hydrogen, C₁₋₄ alkyland C₁₋₄ haloalkyl), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, hydroxy, and C₂₋₈ polyether. Preferably, the substituents onZ are selected from halo, --CO₂ R⁶, --C(O)NR⁶ R⁷, and C₁₋₄ alkoxy(wherein R⁶ and R⁷ are as defined above).

Suitably, rings A and B are each unsubstituted, or substituted by one tofour substituents selected from those described above. Rings A and B areeach preferably unsubstituted, or substituted by one or two substituentsselected from those described above, most preferably, halo.

The group --E--Z is preferably attached to ring B in a meta or paraposition relative to group Y; most preferably, in the para position.

Compounds of formula (I) in which:

W is C₃₋₇ alkyl optionally substituted as described above;

X is --C(O)NR² --, --NR¹ C(O)--, or --NR¹ C(O)NR² -- (wherein R¹ and R²are as defined for formula (I));

Y is ethylene, ethenylene, ethenylene, --O--, --S--, --CH₂ O--, or--OCH₂ --;

E is --O--, --OCH₂ --, --CH₂ O--, a bond, --C(O)N(R³)--, --(R³)NC(O)--,--S--, --S(O)--, --S(O)₂ --, --(R³)NS(O)₂ --, --S(O)₂ N(R³)--,--(R³)NC(O)N(R⁴)--, or --C(O)--(wherein R³ and R⁴ are as defined forformula (I)); and

Z is a 5-or 6-membered saturated ring optionally containing one, two, orthree groups selected from --N(R⁵)-- (wherein R⁵ is selected fromhydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl), --C(O)--, and --O--, or Z isC₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, or aryl and is optionally substitutedas described in formula (I).

and salts, solvates, and physiologically functional derivatives thereofare preferred.

Compounds of formula (I) in which:

W is C₃₋₅ alkyl, for example tert-butyl;

X is --C(O)NH--;

Y is ethenylene or --O--;

E is --O--, or a bond;

Z is a 5-or6-membered saturated ring optionally containing one, two, orthree groups selected from --N(R⁵)-- (wherein R⁵ is selected fromhydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl), --C(O)--, and --O--, or Z isC₁₋₄ alkyl, or C₁₋₄ alkoxy and Z is optionally substituted as describedin formula (I); and

the group --E--Z is attached to ring B in the para position relative togroup Y; and salts, solvates, and physiologically functional derivativesthereof, are particularly preferred.

Particularly preferred compounds within the scope of formula (I)include:

N-{2,4-Difluoro-6-4-(1-carbamoyl-1-methylethyl)phenoxy!phenyl}pivalamide;

N-{2,4-Difluoro-6-4-(2,6-dioxo-4-piperidinyl)phenylethynyl!phenyl}pivalamide;

N- 2-Fluoro-6-(4-trifluoromethoxyphenoxy)phenyl!pivalamide;

N-{2,4-Difluoro-6-4-4-methoxytetrahydropyranyl)phenylethynyl!phenyl}pivalamide;

N-{2,4-Difluoro-6- 4-2,6-dioxo4-piperidinyl)phenoxy!phenyl}pivalamide;

N-{6-4-(1-Carbamoyl-1-methylethoxy)phenylethynyl!-2,4-dilfluorophenyl}pivalamide;

N-{6-4-(1-Carbamoyl-1-methylethyl)phenylethynyl!-2,4-difluorophenyl}pivalamide;

1- 4-(3-Fluoro-2-pivalamidophenoxy)phenyl!cyclopentane-1-carboxylicacid; and

1- 4-(3-Fluoro-2-pivalamidophenoxy)phenyl!cyclopentane-1carboxamide;

or a salt, solvate, or a physiologically functional derivative thereof

Salts of compounds suitable for use in medicine are those which arepharmaceutically acceptable. However, non-pharmaceutically acceptablesalts are within the scope of the present invention for use asintermediates in the preparation of the compounds of the invention andtheir pharmaceutically acceptable salts, solvates, and physiologicallyfunctional derivatives.

Salts according to the invention include ammonium salts, alkali metalsalts, such as those of sodium and potassium, alkaline earth metalsalts, such as those of calcium and magnesium, salts with organic bases,such as triethanolamine, N-methyl-D-glucamine, piperidine, pyridine,piperazine, and morpholine, and salts with amino acids, such as arginineand lysine. Examples of pharmaceutically acceptable acid addition saltsinclude those derived from mineral acids, such as hydrochloric,hydrobromic, phosphoric, metaphosphoric, nitric, and sulphuric acids,and organic acids, such as tartaric, acetic, trifluoroacetic, citric,malic, lactic, fumaric, benzoic, glycollic, gluconic, succinic andmethanesulphonic and arylsulphonic, for example p-toluenesulphonic,acids.

By the term "physiologically functional derivatives" is meant chemicalderivatives of compounds-of formula (I) which have the samephysiological function as the free compound of formula (I), for example,by being convertible in the body thereto. According to the presentinvention, examples of physiologically functional derivatives includeesters, for example, compounds of formula (I) in which a carboxylic acidor hydroxyl group has been functionalised as an ester. Suitable estersinclude carboxylic acid esters such as alkyl, cycloalkyl, alkoxyalkyl,optionally substituted aryl and aralkyl esters, sulphonate esters, aminoacid esters, and mono-, di-, or tri-phosphate esters. In such esters anyalkyl moiety advantageously contains from 1 to 6 carbon atoms,preferably, 1 to 4 carbon atoms; any cycloalkyl moiety advantageouslycontains from 3 to 6 carbon atoms; and any aryl moiety advantageouslycomprises a phenyl group.

The amount of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof which is required to achieve the desired therapeutic effect willof course, depend on a number of factors, for example, the specificcompound chosen, the use for which it is intended, the mode ofadminisration, and the clinical condition of the recipient. In general,a daily dose is expected to lie in the range of from 1 μg to 100 mg,typically from 50 μg to 50 mg, per day per kilogram bodyweight, forexample, 0.1-20 mg/kg/day. Unit doses may contain, for example, from 70μg to 1 g of the active compound. Thus orally administrable unit doseformulations, such as tablets or capsules, may contain, for example,from 3.5 mg to 500 mg, typically from 7 mg to 500 mg. In the case ofpharmaceutically acceptable salts, the weights indicated above refer tothe weight of the diaryl ion derived from the salt.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof, in the manufacture of a medicament forthe prophylaxis or treatment of a clinical condition for which an ACATinhibitor is indicated, such as hyperlipidaemia or atherosclerosis.

Whilst it is possible for the compounds of formula (I), orpharmaceutically acceptable salts, solvates, or physiologicallyfunctional derivatives thereof to be administered alone, it is preferredto present them in the form of a pharmaceutical formulation.

Accordingly, the present invention further provides a pharmaceuticalformulation comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof, and a pharmaceutically acceptable carrier or excipient.

The carrier or excipient must, of course, be acceptable in the sense ofbeing compatible with the other ingredients of the formulation and mustnot be detrimental to the recipient. The carrier or excipient may be asolid or a liquid, or both, and is preferably formulated with thecompound as a unit-dose formulation, for example, a tablet, which maycontain from 0.05% to 95% by weight of the active ingredient. Otherpharmacologically active substances may also be present including othercompounds of formula (I) and pharmaceutically acceptable salts,solvates, and physiologically functional derivatives thereof Theformulations of the invention may be prepared by any of the well knowntechniques of pharmacy consisting essentially of admixing thecomponents.

The formulations of the present invention include those suitable fororal, rectal, topical, buccal (e.g. sub-lingual) and parenteral (e.g.subcutaneous, intramuscular, intradermal or intravenous) administration,although the most suitable route in any given case will depend on thenature and severity of the condition being treated and on the nature ofthe particular compound of formula (I), or a pharmaceutically acceptablesalt, solvate, and physiologically functional derivative thereof whichis being used.

Hereinafter, the term active ingredient means a compound of formula (I)or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of the active ingredient; as a powderor granules; as a solution or a suspension in an aqueous or non-aqueousliquid; or as an oil-in-water or water-in-oil emulsion. As indicated,such formulations may be prepared by any suitable method of pharmacywhich includes the step of bringing into association the activeingredient and the carrier or excipient (which may constitute one ormore accessory ingredients). In general, the formulations are preparedby uniformly and intimately admixing the active ingredient with a liquidor finely divided solid carrier, or both, and then, if necessary,shaping the product. For example, a tablet may be prepared bycompressing or moulding a powder or granules of the active ingredientoptionally with one or more assessory ingredients. Compressed tabletsmay be prepared by compressing, in a suitable machine, the activeingredient in a free-flowing form, such as a powder or granulesoptionally mixed with a binder, lubricant, inert diluent and/or surfaceactive/dispersing agent(s). Moulded tablets may be made by moulding, ina suitable machine, the powdered active ingredient moistened with aninert liquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising the active ingredient in a flavoured base, usuallysucrose and acacia or tragacanth, and pastilles comprising the compoundin an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations of the present invention suitable for parenteraladministration conveniently comprise sterile aqueous preparations of theactive ingredient, preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also be effected by means of subcutaneous,intramuscular, or intradermal injection. Such preparations mayconveniently be prepared by admixing the active ingredient with waterand rendering the resulting solution sterile and isotonic with theblood. Injectable compositions according to the invention will generallycontain from 0.1 to 5% w/w of the active ingredient.

Formulations suitable for rectal administration are preferably presentedas unit-dose suppositories. These may be prepared by admixing the activeingredient with one or more conventional solid carriers, for example,cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosol,or oil. Carriers and excipients which may be used include vaseline,lanoline, polyethylene glycols, alcohols, and combinations of two ormore thereof The active ingredient is generally present at aconcentration of from 0.1 to 15% w/w of the composition, for example,from 0.5 to 2%.

According to a flurther aspect, the present invention also provides aprocess for the preparation of compounds of formula (I), or a salt,solvate, or a physiologically functional derivative thereof, whichcomprises a method well known to those skilled in the art, for example,as described below.

In general, compounds of formula (I) and salts, solvates, andphysiologically functional derivatives thereof, may be prepared bycoupling a compound of formula (II) with a compound of formula (III);##STR3## wherein, Y' and Y" are groups capable of reacting together toform the desired linkage Y (as defined for formula (I)), as discussedbelow;

(WX)'-- is either the group W--X-- (wherein W and X are as defined forformula (I)), a protected form thereof or a precursor for the said groupW--X--, as discussed below;

--(EZ)' is either the group --E--Z (wherein E and Z are as defined forformula (I)), a protected form thereof or a precusor for the said group--E--Z, as discussed below;

and rings A and B are optionally substituted as described for formula(I)

to give either a compound of formula (I) or a compound of formula (IV):##STR4## wherein Y is as defined for formula (I), (WX)'-- and --(EZ)'are as defined for formulae (I) and (III) respectively (excludingcombinations of (WX)'-- and --(EZ)' which give a compound of formula(I)), and rings A and B are optionally substituted as described forformula (I);

followed by,

(i) When (WX)'-- in the compound of formula (IV) is a precursor for thegroup W--X--, formation of the group W--X-- (wherein W and X are asdefined for formula (I)), as discussed below; and/or

(ii) When --(EZ)' in the compound of formula (IV) is a precursor for thegroup --E--Z; formation of the group --E--Z (wherein E and Z are asdefined for formula (I)), as discussed below, and/or

(iii) Removal of any protecting groups; and/or

(iv) Optional formation of a salt, solvate, or physiologicallyfunctional derivative of the resulting compound of formula (1), as didbelow or conversion to a different compound of formula (I).

When Y in the compound of formula (I) is to be a bond; Y' and Y" aregroups capable of reacting together to provide a direct bond betweenring A of the compound of formula (I) and ring B of the compound offormula (III). Suitably, one of Y' and Y" may be --B(OH)₂, and the othera leaving group, for example a halo group (typically bromo or iodo) or asulphonate such as an alkylsulphonate (typically, methylsulphonate), anarylsulphonate (typically, tolylsulphonate), or a haloasulphonate(typically, trifluoro-methanesulfonate); the coupling could then beeffected under the conditions described in Tetrahedron Lett., 1987, 28,5093, for example, in the presence of a suitable catalyst, for example,tetrakis (triphenylphosphine) palladium (0) and an inorganic base, forexample, sodium carbonate at elevated temperature, such as 50°-150°C.Alternatively, one of Y' and Y" may be an organometallic group, forexample, --MgX' or --ZnX where X is a halogen, and the other a leavinggroup (as defined above); the coupling could then be effected by analogywith the teaching of Tetrahedron Lett., 1980, 21, 845, Chem. Lett. 1975,133, and Synth. Commun., 1991, 21. 481, for example, in an inertsolvent, such as, TBF, in the presence of a catalyst, such as,1,4-bis(diphenylphosphine)butane palladium (0) dichloride, palladiumacetate, or tetrakistriphenyl phosphine palladium (0), at non-extremetemperature, such as 0°-600° C.

When Y in the compound of formula (I) is to be --(CH₂)_(n)--O--(CH₂)_(p--) or --(CH₂)_(n) --S--(CH₂)_(p) -- (wherein n and p areas defined for formula (I)); Y' and Y" are groups capable of reactingtogether to provide such a linkage between ring A of the compound offormula (II) and ring B of the compound of formula (II). Suitably, oneof Y' and Y" may be --(CH₂)_(n) --L (wherein n is as defined for formula(I) and L is a leaving group as defined above), and the othera--(CH₂)_(p) --OH or --(CH₂)_(p) --SH group (wherein p is as defined forformula (I)); such a reaction could be effected by treatment with abase, such as a hindered base, for example potassium tert-butoxide, or ametal hydride, for example, sodium hydride, in an aprotic solvent, forexample N,N-dimethylformamide at a non-extreme temperature, such as,-10° C. to 50° C.

When Y in the compound of formula (I) is to be --(CH₂)_(n)--S(O)--(CH₂)_(p) -- or --(CH₂)_(n) --S(O)₂ --CH₂)_(p) -- (wherein n andp are as defined for formula (I)) the process may be the same as thatdescribed above for when Y is --(CH₂)_(n) --S--(CH₂)_(p) -- followed byoxidation of the linking sulphur, suitably by treatment with a peroxygencompound, for example, m-chloroperbenzoic acid in an inert solvent, forexample, dichloromethane at low temperature, such as -50° C. to 50° C.

When Y in the compound of formula (I) is to be C₁₋₄ alkynylene; Y' andY" are groups capable of reacting together to form such a linkagebetween ring A of the compound of formula (II) and ring B of thecompound of formula (III). For example, when Y in the compound offormula (I) is to be --C.tbd.C--, one of Y' and Y" may be --C.tbd.CH andthe other a leaving group (as defined above); the coupling may beeffected in the presence of a catalyst system, for example, palladium(O) tetra(triphenylphosphine)/copper (I) iodide/triphenylphosphine, inthe presence of an organic base, such as piperidine or a trialkylamine,for example triethylamine, at non-extreme temperature, such as -10° C.to 50° C. Other alkynylene linkages may be formed using the appropriatecompounds of formulae (II) and (III) as would be apparent to the personskilled in the art.

When Y in the compound of formula (I) is to be C₁₋₄ alkenylene or C₁₋₄alkylene the process may be the same as that described above for when Yis C₁₋₄ alkynylene, followed by reduction under suitable conditions,such as chemical or catalytic hydrogenation, for example, treatment witha transition metal catalyst, for example, palladium dibenzyladineacetone (Pd(dba)₂), in an aprotic solvent, for example,dimethylsulphoxide, or treatment with H₂ in the presence of an inertsolvent and a hydrogenation catalyst, for example, palladium oncharcoal, at a non-extreme temperature, such as -10° C. to 50° C.

Conversion (i) may be effected in a number of ways, depending on thenature of group X in the compound of formula (I):

(a) When X is to be --NR¹ C(O)NR² -- (wherein R¹ and R² are as definedfor formula (I)), the group (WX)'-- in the compound of formula (II) issuitably an isocyanate (O═C═N--) group. The compound of formula (IV)formed after reaction with the appropriate compound of formula (III) maythen be treated with a compound of formula W--NHR¹ (wherein W and R¹ areas defined for formula (I)), typically in a non-polar solvent, forexample tetrahydrofuran or benzene, in the presence of an organic base,for example N,N,dimethylaminopyridine (DMAP), at a moderate temperature,for example, in the range 10° C. to 50° C., suitably at ambienttemperature. The resulting urea group may optionally be N-alkylatedaccording to conventional methods to give the desired W--NR¹ C(O)NR²--group (wherein W, R¹, and R² are as defined for formula (I));

(b) When X is to be --NR¹ C(O)-- or --C(O)NR² -- (wherein R¹ and R² areas defined for formula (I)), the group (WX)'--in the compound of formula(II) is suitably a carboxylic acid derivative i.e. LC(O)-- (wherein L isa leaving group as defined above) or an amine ie HNR² -- (wherein R² isas defined for formula (I)). The compound of formula (IV) formed afterreaction with the appropriate compound of formula (III) may then betreated with a compound of formula W--NR¹ H or W--C(O)L respectively(wherein W and R¹ are as defined for formula (I) and L is a leavinggroup as defined above), typically in a non-polar solvent, for example,a halogenated hydrocarbon, such as dichloromethane, an ether, oracetonitrile; in the presence of an organic base, for example, pyridine,DMAP, or a trialkylamine such as triethylamine, at a moderate or reducedtemperature, for example, in the range -30° C. to 50° C., suitably atambient temperature or below

(c) When X is to be --NR¹ C(O)O-- or --OC(O)NR² -- (wherein R¹ and R²are as defined for formula (I)), the group (WX)'-- in the compound offormula (II) is suitably a hydroxyl group or an isocyanate grouprespectively. The compound of formula (IV) formed after reaction withthe appropriate compound of formula (III) may then be treated with acompound of formula W--N═C═O or W--OH respectively (wherein W is asdefined for formula (I)), typically under the conditions described inpart (a) above. The resulting urethane group may optionally beN-alkylated according to conventional methods to give the desired W--NR¹C(O)O-- or W--OC(O)NR² -- group (wherein W, R¹, and R² are as definedfor formula (I)).

Conversion (ii) may be effected in a number of ways, depending on thenature of group E in the compound of formula (I):

(d) When E is to be a bond or C14 alkylene, the group --(EZ)' in thecompound of formula (III) is suitably a halogen. The compound of formula(IV) formed after reaction with the appropriate compound of formula (II)may then be treated with a strong base such as butyllithium, in anon-polar solvent, for example tetrahydrofuran, at low temperature, forexample -90° C. to -50° C., to form an anion on ring B. The anion maythen be treated in situ with a compound contaning an electrophilic ire,such as a ketone, which on reaction with the anion forms the desiredgroup --E--Z (as defined for formula (I)). For example, when the group--E--Z is to be 4-hydroxytetrahydropyran-4-yl, the anion on ring B maybe reacted with tetrahydro-4H-pyran4one; in a non-polar solvent, such astetrahydrofuran; at reduced temperate, for example -90° C. to -50° C.;

(e) When E is to be --(CH₂)_(r) --O--(CH₂)_(s) or --(CH₂)_(r)S--(CH₂)s--(wherein r and s are as defined for formula (I)), the group--(EZ)' in the compound of formula (III) is suitably --(CH₂)_(r) OH or--(CH₂)_(r) SH (wherein r is as defined above), or a protected formthereof The compound of formula (IV) formed after reaction with theappropriate compound of formula (II) may then be treated with a compoundof formula L--(CH₂)_(s) --Z (wherein L is a leaving group, as definedabove, and s and Z are as defined for formula (I)), this reaction may beeffected in conditions analogous to those described above for theformation of linkage Y, when Y is to be --(CH₂)_(n) --O--(CH₂)_(p) -- or--(CH₂)_(n) --S--(CH₂)_(p) -- (wherein Y, n, and p are as defined forformula (I));

(f) When E is to be --(CH₂)_(r) --S(O)--(CH₂)_(s) or --(CH₂)_(r) S(O)₂--(CH₂)_(s) -- (wherein r and s are as defined for formula (I)) theprocess may be the same as that described above for when E is--(CH₂)_(r) --S--(CH₂)_(s) --, followed by oxidation of the linkingsulphur, suitably by treatment with a peroxygen compound, for example,m-chloroperbenzoic acid in an inert solvent, for example,dichloromethane;

(g) When E is to be --(CH₂)_(r) --C(O)--(CH₂)_(s) -- (wherein r and sare as defined for formula (I)), the group --(EZ)' in the compound offormula (III) is suitably --(CH₂)_(r) C(O)L (wherein r is as defined forformula (I) and L is a leaving group as defined above). The compound offormula (IV) formed after reaction with the appropriate compound offormula (II) may then be reacted with an anion of formula --(CH)_(s) --Z(wherein s and Z are as defined for formula (I)), typically in situafter formation of the anion by treatment of the corresponding organichalide with a strong base such as butyl lithium, in a non-polar solvent,for example tetrahydrofuran, at low temperature, for example -90° C. to-50° C.;

(h) When E is to be --S(O)₂ N(R³)-- or --(R³)NS(O)₂ -- (wherein R³ is asdefined for formula (I)), the group --(EZ)' in the compound of formula(III) is suitably --S(O)₂ L or --N(R³)H respectively (wherein L is aleaving group as defined above and R³ is as defined for formula (I)) ora protected form thereof The compound of formula (IV) formed afterreaction with the appropriate compound of formula (II) may then betreated with a compound of formula HN(R³)--Z or L--S(O)₂ --Zrespectively (wherein L is a leaving group as defined above and R³ and Zare as defined for formula (I)), typically in an inert solvent, such asa halogenated hydrocarbon for example dichloromethane, in the presenceof an organic base, such as a trialkylamine, for example, triethylamine,at a moderate or reduced temperature, for example, in the range -3020 C.to 5020 C., suitably at ambient temperature or below;

(i) When E is to be --C(O)N(R³)-- or --(R³)NC(O)-- (wherein R³ is asdefined for formula (I)), the group --(EZ)' in the compound of formula(III) is suitably a carboxylic acid derivative or an amine respectively,as defined above. The compound of formula (IV) formed after reactionwith the appropriate compound of formula (II) may then be treated with acompound of formula Z--NR³ H or Z--C(O)L respectively (wherein Z and R³are as defined for formula (I) and L is a leaving group as definedabove), typically under the conditions described for conversion (i)(b)above. For example, when E is to be --C(O)NH--, the group --(EZ)' in thecompound of formula (III) is suitably --COCl and may be reacted with acompound of formula Z--NH₂ (wherein Z is as defined for formula (I)).

(j) When E is to be --(R³)NC(O)N(R⁴)-- (wherein R³ and R⁴ are as definedfor formula (I)). The group --(EZ)' in the compound of formula (III) issuitably an isocyanate or --N(R³)H group. The compound of formula (IV)formed after reaction with the appropriate compound of formula (II) maythen be treated with a compound of formula Z--NHR⁴ or Z--NCOrespectively (wherein Z and R⁴ are as defined for formula (I)),typically under the conditions described for conversion (i)(a) above.The resulting urea group may optionally be N-alkylated according toconventional methods to give the desired--(R³)NC(O)N(R⁴)Z group (whereinZ, R³, and R⁴ are as defined for formula (I)).

Optional conversion (iv) may be carried out as follows:

Conversion of a compound of formula (I) to a corresponding salt may beeffected by reaction with the appropriate acid or base. Conversion to aphysiologically functional derivative, such as an ester, may be carriedout by methods well known to a skilled man or readily available from thechemical literature.

Alternatively, group (WX)'-- in the compound of formula (II) and/orgroup --(EZ)' in the compound of formula (III) may be converted to therespective group W--X-- or --E--Z (as defined for formula (I)), or aprotected form thereof before reacting the compounds of formulae (II)and (III) together to form the compound of formula (IV) (as defined forformula (I)). Such conversions may be effected by carrying out reactionsanalogous to those described in (a) to (j) above.

Compounds of formula (II) in which (WX)'--is a precursor for the groupW--X--(as discussed above); for example, an isocyanate, carboxylic acidderivative, amine, or hydroxyl group; are commercially available or maybe prepared by methods well known to those skilled in the art or methodsreadily available from the chemical literature. For example, where thecompound of formula (II) required is a substitued aniline, it may becommercially available, or be prepared from the correspondingcommercially available nitro compound by reduction, for example, bycatalytic hydrogenation, in an inert solvent, for example, in thepresence of palladium on charcoal or by chemical reduction, for example,with zinc dust.

Compounds of formula (III) in which--(EZ)' is a precursor for the group--E--Z (as discussed above; for example, a halogen, hydroxyalkyl,thioalkyl, carboxylic acid derivatively, sulphonic acid derivative,amine, or isocyanate group; are commercially available or may beprepared by methods well known to those skilled in the art or methodsreadily available from the chemical literature.

The reagents used to convert (WX)'-- and --(EZ)' into W--X-- and --E--Zrespectively (as described above) are all commercially available or maybe prepared by methods well known to those skilled in the art or methodsavailable from the chemical literature.

At any stage of the process, certain functional groups may be chemicallyprotected to prevent them being altered during chemical reaction at adifferent functional group on the molecule, as is well known to thoseskilled in the art. For example, where (WX)'-- in the compound offormula (II) is an amine, it may be preferable to protect it (forexample, with an alkoxycarbonyl group, such as tert-butoxycarbonyl),with subsequent deprotection by any appropriate method (for example, byacid hydrolysis). Other such methods of protection and deprotection arewell known to those skilled in the art.

The present invention also provides novel intermediates of formula (II),as defined above; particularly a compound selected from:

N-(2-Bromo-4,6-difluorophenyl)pivalamide,

N- 2,4-Difluoro (trimethylsilylethyl)phenyl!pivalamide.

N-(2,4-Difluoro-6(ethynylphenyl)pivalamide; and

N-(2-Bromo-4,6difluorophenyl)pivalamide.

The present invention also provides novel intermediates of formula(III), as defined above, particularly a compound selected from:

3-(4-Benzyloxyphenyl) glutaric acid;

4-(4-Benzyloxyphenyl) glutarimide;

4-(4-Hydroxyphenyl) glutarimide;

Methyl 2-(4-methoxyphenyl)-2-methylpropanoate;

2-(4-Hydroxyphenyl)-2-methylpropanoic acid;

Methyl 2-(4-hydroxyphenyl)-2-methylpropanoate;

3-(4-Bromophenyl) glutaric acid;

4-(4-Bromophenyl) glutarimide,

4-(4Iodophenyl) glutarimide;

4-(4-Bromophenyl)-4-hydroxytetrahydropyran;

4-(4-Bromophenyl)-4-methoxytetrahydropyran;

4-(4-Trimethylsilylethynylphenyl)-4-methoxytetrahydropyran;

4-(4-Ethynylphenyl)-4-methoxytetrahydropyran;

Ethyl 2-(4-iodophenoxy)-2-methylpropanoate;

Ethyl (4-bromophenyl)ethanoate;

Ethyl 2-(4-bromophenyl)-2-methylpropanoate; and

Ethyl 2-(4-iodophenyl)-2-methylpropanoate.

The present invention also provides novel intermediates of formula (IV),as defined above; particularly a compound selected from:

2,4-Difluoro-6- 4-(2,6-dioxo-4-piperidinyl)phenoxy!-5-nitrobenzene;

2,4-Difluoro-6- 4-(2,6-dioxo-4-piperidinyl)phenoxy!-5-aminobenzene;

2-Fluoro-6-(4-trifluoromethoxyphenoxy) aniline;

Methyl 2-{4- 3,5-difluoro-2-nitrophenoxy!phenyl}-2-methylpropanoate; and

Methyl 2-{4- 2-amino-3,5-difluorophenoxy!phenyl}-2-methylpropanoate.

Certain compounds of formula (I) are also useful as intermediates in thepreparation of other compounds of formula (I), for example a compoundselected from:

Methyl 2-4-(3,5-difluoro-2-pivalamidophenoxy)phenyl!2-melthylpropanoate;

2- 4-(3,5-Difluoro-2-pivalamidophenoxy)phenyl!-2-methylpropanoic acid;

Ethyl 2-4-(3,5-difluoro-2-pivalamidophenylethynyl)phenoxy!-2-methylpropanoate;

2- 4-(3,5-Difluoro-2-pivalamidophenylethynyl)phenoxy!-2-methylpropanoicacid;

Ethyl 2- 4-(3,5-difluoro-2-pivalamidophenylethynyl)phenyl!-2-methylpropanoate; and

2- 4-(3,5-Difluoro-2-pivalamidophenylethynyl)phenyl!-2-methyl propanoicacid.

For a better understanding of the invention, the following Examples aregiven by way of illustration. All final products analysed correctly andgave nmr spectra consistent with the assigned structures.

SYNTHETIC EXAMPLE 1 Preparation of N-{2,4-Difluoro-6-4-(2,6-dioxo-4-piperidinyl)phenoxy!phenyl}-pivalamide

(a) 3-(4-Benzyloxyphenyl) glutaric acid

4-Benzyloxybenzaldehyde (50.0 g, Aldrich), ethyl acetoacetate (61.31 g,Aldrich), and piperidine (4.01 lg) were reacted together overnight. Theresulting mixture was refluxed for 3-4 hours with ethanol (400 ml) andsodium methoxide (63.63 g).

On removal of the solvent in vacuo, the residue was washed twice withdiethyl ether, and filtered. The solid was taken up in water (500 ml),filtered, and the filtrate acidified with concentrated HCl to give ayellow precipitate. Recrystallisation from ethyl acetate gave the titleproduct.

Microanalysis: C₁₈ H₁₈ O₅ % found (calculated) C69.59(68.79), H 5.81(5.77), N 0.05 (0.00).

(b) 4-(4-Benzyloxyphenyl)glutarimide

The product from Example 1(a) (10.0 g) was dissolved in 0.88 ammoniasolution, then dried in vacuo. The residue was heated at 200-210° C. for14 hours until NH₃ evolution had ceased and reaction was complete. Oncooling, the reaction mixture was recrystallised from ethyl acetate togive the title product as a beige solid.

Microanalysis: C₁₈ H₁₇ NO₃ C 73.82 (73.20), H 6.22 (5.80), N 4.68(4.74).

(c) 4-(4-Hydroxyphenyl)glutarimide

The product from Example 1(b) (2.76 g) was mixed with ethyl acetate (150ml), and palladium on charcoal (500 mg) was added. The mixture wastreated with H₂ at atmospheric pressure until gas uptake ceased andreaction was complete. The reaction mixture was filtered through Hyflo(Trademark) and the solvent was removed from the filtrate in vacuo togive the crude title product as a white solid, which was thenrecrystallised from ethanol.

Thin Layer Chromatography (SiO₂ ; Dichloromethane/ethanol 19:1): Rf0.33

(d) 2,4-Difluoro-6- 4-(2,6-dioxo-4-piperidinyl)phenoxy!-5-nitrobenzene

A solution of the product from Example 1(c) (10 g) was added slowly to asuspension of washed sodium hydride (117 mg) in tetrahydrofuran (THF).When the reaction was complete, the resulting suspension wasconcentrated to half volume and then added slowly to a solution of2,4,6-trifluoronitrobenzene (1.29 g, Aldrich) in N,N-dimethylformamide(DMF). After 30 minutes at room temperature, the reaction was quenchedwith water and extracted 3 times with ethyl acetate. The combinedorganic phases were washed with water then dried over MgSO₄, filtered,and the solvent was removed in vacuo to give the crude title compound asa pale yellow solid which was then purified by flash columnchromatography on silica, eluting with ethyl acetate/methanol (99.1).

(e) 2.4-Difluoro-6- 4-(2,6-Dioxo-4-Piperidinyl)Phenoxy!-5-Aminobenzene

To a mixture of the product from Example 1(d) (620 mg) in THF (15 ml),was added palladium on charcoal (60 mg) and 30% aqueous sodiumhypophosphite (30 ml). The reaction was stirred for 2-3 hours, thenfiltered through Hyflo, poured into water then extracted twice withethyl acetate. The combined organic phases were dried on MgSO₄,filtered, and the solvent was removed in vacuo to yield a white solid.Purification by flash column chromatography on silica, eluting withdichloromethane/methanol (19:1) afforded the title product.

(f) N-{2,4-Difluoro-6-4-(2,6-Dioxo-4-piperidinyl)Phenoxy!Phenyl}Pivalamide

To a solution of the product from Example 1(e) (340 mg) in THF (10 ml)was added triethylamine (124 mg) and pivaloyl chloride (148 mg,Aldrich). The reaction was stirred overnight at room temperature, withthe exclusion of moisture. After filtration through Hyflo, the filtratewas evaporated in vacuo to give an oil. The oil was dissolved in ethylacetate and washed successively with water (×2), saturated NaHCO₃ (×2),then water (×2). The organic layer was dried over MgSO₄, filtered andthe solvent removed in vacuo. After trituration with ethylacetate/hexane/ether and removal of the solvent in vacuo, the crudetitle product was obtained as a white solid. Purification by preparativeHPLC on silica, eluting with hexane/ethanol (9:1) afforded pure titleproduct, mp 172° C.

SYNTHETIC EXAMPLE 2 Preparation of N-2-Fluoro-6-(4-Trifluoromethoxyphenoxy)Phenyl!Pivalamide

(a) 2-Fluoro-6-(4-Trifluoromethoxyphenoxy)Nitrobenzene

To a solution of trifluoromethoxyphenol (35.0 g, Lancaster) in methanolwas added a solution of potassium-t-butoxide (22.48 g) in methanol(total volume of solvent 150 ml). The reaction was stirred at roomtemperature for 30 mins., then the solvent was removed in vacuo to givethe phenolate as an off-white solid.

The phenolate was dissolved in DMF (φml) and added slowly to a solutionof 2,6-difluoronitrobenzene (34.39 g, Aldrich) in DMF (100 ml). Afterstirring overnight at room temperature, the reaction was poured intodilute NaOH and extracted 3 times with diethyl ether. The combinedethereal fractions were washed sequentially with dilute NaOH (×2), thenwater (×2), dried over MgSO₄, and the solvent removed in vacuo to givethe title product.

(b) 2-Fluoro-6-(4-Trifluoromethoxyphenoxy)Aniline

To a solution of the product from Example 2a (30.0 g) in THF (150 ml)was added 10% palladium on charcoal (500 mg) then sodium phosphinate(100 g) in water (200 ml). Cooling was used to keep the reaction undercontrol. After 1 hour the reaction mixture was filtered through Hyflo,the filtrate poured into water then extracted twice withdichloromethane. The combined organic phases were washed twice withwater then dried on MgSO₄, filtered and the solvent removed in vacuo togive a pale yellow oil. Purification by flash column chromatography onsilica, eluting with hexane/ethyl acetate (4:1) afforded the titlecompound.

Thin Layer Chromatography (SiO₂ ; Hexane/Ethyl Acetate 4:1) : Rf 0.48

(c) N- 2-Fluoro-6-(4-Trifluoromethoxyphenoxy) Phenyl!Pivalamide

To a solution of the product from Example 2(b) (20.0 g) in diethyl ether(100 ml), was added triethylamine (8.46 g), then a solution of pivaloylchloride (10.08 g, Aldrich) in diethyl ether (100 ml). The reaction wasstirred at room temperature overnight, then filtered. The filtrate waswashed twice with water, then twice with saturated NaHCO₃, then twicewith water. The organic phase was dried over MgSO₄, filtered then thesolvent was removed in vacuo to give the crude product as a fawn solid.Recrystallisation from hexane/ethyl acetate (9:1) afforded the titlecompound as a white solid.

¹ H-NMR (d₆ -DMSO)δ : 8.9 (s, 1H , NH ), 7.35 (d, 2H, ArH), 7.35 (m, 1HArH), 7.20 (td, 1H, ArH), 7.0 (m, 1H, ArH), 6.98 (d, 2H ArH), and 1.0(s, 9H, ^(t) Bu).

SYNTHETIC EXAMPLE 3 Preparation of N-{2.4-Difluoro-6-4-(1-Carbamoyl-1-Methylethyl) Phenoxy!Phenyl}-Pivalamide

(a) Methyl 2-(4-Methoxyphenyl)-2-Methylpropanoate.

To a stirred slurry of sodium hydride (22.4 g) in ethylene glycoldimethyl ether (250 ml) under N₂ was added a solution of methyl4-methoxyphenylacetate (25 g, Aldrich) and methyl iodide (35 ml,Aldrich) in ethylene glycol dimethyl ether (50 ml) over approx. 15minutes. Refluxing was continued overnight before most of the solventwas removed by distillation at reduced pressure. The resulting solid wascooled in an ice bath and diethyl ether (250 ml) added. After stirring,water (150 ml) was slowly added, before the two layers were separated.The ether layer was extracted with water (2×150 ml) before being dried(MgSO4) and the solvent removed in vacuo to give an orange oil.Purification was by distillation to give the title compound as acolourless oil (19.5 g) ; b.pt. 74° C. at 0.12 lm/Hg.

(b) 2-(4-Hydroxyphenyl)-2-Methylpropanoic Acid

The product from Example 3(a) (10.0 g) was dissolved in dichloromethane(100 ml) at -700° C. A solution of boron tribromide (1M in DCM ; 82 ml,Aldrich) was added dropwise through an air condenser. A calcium chloridetube was then fitted and the reaction left stirring overnight to attainroom temperature. From this mixture was obtained a brown solution whichwas hydrolysed by shaking with water (150 ml). Diethyl ether (500 ml)was then added and the organic layer separated. The organic layer wasextracted with 2M NaOH (250 ml) and then this extract neutralised with2M HCI. This combined layer was extracted into diethyl ether (300 ml)which was dried (MgSO₄) and then the solvent removed in vacuo to givethe title compound as a crude brown oil (7.73 g).

(c) Methyl 2-(4-Hydroxyphenyl)-2-Methylpropanoate

The product from Example 3(b) (7.72 g) was dissolved up in methanol atroom temperature. To this was added p-toluenesulphonic acid (0.25 g) andthe reaction heated to reflux overnight. On completion the methanol wasremoved by distillation and the residue taken up in diethyl ether (200ml). The diethyl ether layer was washed with water (200 ml) and dried(MgSO4) before the solvent was removed in vacuo to give a pale brownsolid. Purification was by chromatography on silica (Merck) eluting withDCM diethyl ether (95:5) to give the title compound as a white solid(4.32 g).

(d) Methyl 2-{4- 3,5Difluoro-2-Nitrophenoxy!Phenyl}-2-methylpropanoate

The product from Example 3(c) (4.00 g) was treated with potassiummethoxide (1.47 g) in dimethylformamide (DMF) (80 ml) and stirred atroom temperature for 1 hour. To this was added2,4,6-trifluoronitrobenzene (3.72 g, Aldrich) and the reaction left tostir overnight. On completion the reaction was poured into water (800ml) and extracted with diethyl ether (2×250 ml). The organics werecombined and washed with water (250 ml) and then dried (MgSO4). Afterfiltering, the solvent was removed in vacuo to give a yellow oil.Purification was by chromatography on silica eluting with diethyl ether40/60 petrol (1:2) to give two major components, i.e. the ortho and parasubstituted products. The desired ortho title compound was thus retained(2.2 g).

(e) Methyl 2-{4- 2-Amino-3,5-Difluorophenoxy!Phenyl}-2-Methylpropanoate

The product from Example 3(d) (2.02 g) was dissolved up intetrahydrofuran (THT) (70 ml) with vigorous stirring. To this was addedPd/C (10%) (0.2 g) followed by NaH₂ PO₂.×H₂ O solution (30% aqueoussolution, 80 ml) and the reaction stirred at room temperature for 3hours. On completion the reaction was filtered through `Hyflo` and addedto water (150 ml). This aqueous layer was extracted with diethyl ether(2×150 ml) which was then dried (MgSO4) and the solvent removed in vacuoto give the title compound as a dark brown oil (1.3 lg).

(f) Methyl 2-4-(3,5-Difluoro-2-Pivalamidophenoxy/Phenyl!-2-Methylpropanoate

The product from 3(e) was dissolved in DCM (30 ml) in an ice bath. Tothis was added 4-dimethyl-aminopyridine (DMAP) (50 mg, Aldrich) andpyridine (0.4 g) and the ice bath removed, allowing the reaction to warmto room temperature. Pivaloyl chloride (0.6 g, Aldrich) in DCM (30 ml)was added dropwise and the reaction left to sir under N₂ overnight. Oncompletion the mixture was added to diethyl ether (200 ml) and washedwith 8% citric acid (2×50 ml), water (150 ml) and then dried (MgSO₄).The solution was filtered and the solvent removed in vacuo to give abrown oil. Purification was by chromatography on silica eluting withdiethyl ether: 40/60 petrol (1:1) to give a solid with wasrecrystallised from hot 40/60 petrol to give the title compound as awhite solid (0.60 g); m.p. 103-104° C.

(g) 2- 4-(3.5-Difluoro-2-Pivalamidophenoxy)Phenyl!-2-MethylpropanoicAcid

The product from Example 3(f) (0.51 g) was dissolved up in methanol (8ml) at room temperature with vigorous sting To this was added sodiumhydroxide (60.5 mg) in water (8 ml) and the reaction mixture refluxedfor 4 hours. On completion the mixture was cooled and the methanolremoved by distillation. The resulting aqueous layer was acidified topH═1 using 2M HCl. The white solid was filtered off and washedthoroughly with water to give the title product (0.45 g) ; m.p.168°-170° C.

(h) N-{2,4-Difluoro-6-4-(1-Carbamoyl-1-Methylethyl)Phenoxy!Phenyl}Pivalamide

The product from Example 3(g) (0.32 g) and triethylamine (0.12 ml) werestirred in terahydrofuran (THF) (10 ml) in an ice bath. To this wasadded methylchloroformate (0.08 g, Aldrich) rapidly with continuoussting. After 1 hour anhydrous NH₃ gas was passed through the reactionfor approx. 5 minutes. The mixture was then removed form the ice bath,stirred at room temperature for 1 hour then left standing overnight. Oncompletion the triethylamine and THF were removed in vacuo, the residuetaken up in dichloromethane (150 ml) and then washed with 8% citric acid(100 ml). The acid layer was extracted with DCM and the organic layerscombined and washed with NaHC03 (100 ml) and water (100 ml) before beingdried (MgSO₄). After filtering, the solvent was removed in vacuo to givea colourless oil. Purification was by triturating with 40/60 petrol anda trace of diethyl ether to give the title compound as a white solid(0.25 g); m.p. 169°-170° C.

¹ H-NMR (CDCl₃) δ: 7.20 (q, 4H, Ar--H), 6.80 (s, 1H, NH), 6.70 (m, 1HAr--H), 6.45 (m, 1H, Ar--H), 5.25 (wide s, 2H, NH₂), 1.60 (s, 6H,2×methyl), 1.20 (s, 9H, ^(t) Bu).

SYNTHETIC EXAMPLE 4 Preparation of 1-4-(3,5-Difluoro-2-Pivalamidophenoxy)Phenyl!Cyclopentane-1-Nitrile

(a) 4-(p-Hydroxyphenyl)-1-Cyclopentanecarboxylic Acid

A solution of 1-(p-methoxyphenyl)-1-cyclopentanecarboxylic acid (5 g.Aldrich) in dry dichloromethane (DCM) (100 ml), cooled to -780° C., wastreated (dropwise) under nitrogen with boron tribromide (100 ml) in dryDCM. The mixture was stirred for thirty minutes at -780° C., then atroom temperature (RT) overnight. The reaction mixture was slowly pouredinto ice, DCM was separated, and the aqueous phase was extracted withDCM (3×20 ml). The organic extracts were combined, washed with saturatedbrine, dried over sodium sulphate, filtered and evaporated in vacuo toafford the phenol as a white solid.

¹ H NMR (DMSO): δ 5 1.5-1.8 (m, ₆ H,CH₂ CH₂ CH₂ CH₂); 2.4-2.6 (m, 2H,CH₂ CH₂ CH₂ CH₂); 6.7 (dd, 2H, aryl); 7.1(dd, 2H aryl); 9.3 (broadsinglet, 1HI, OH); 12.0 (broad singlet, 1H COOH).

(b) 1-(p-Hydroxyphenyl)-1Cyclopentanecarboxamide

1-Hydroxybenzotriazole (3.68 g, Aldrich),1-Ethyl-3-(3-Dimethylaminopropyl)-carbodiimide hydrochloride (5.28 gSigma) and N-Methylmorpholine (2.78 g, Aldrich) were added, undernitrogen, to a stirred solution of the product from Example 4(a) (5.0 g)in dry tetrahydrofuran (THF). The mixture was stirred at RT for fourhours, then slowly added to liquid ammonia (excess) at -60° C. After onehour, the mixture was warmed to RT and stirred overnight.

THF was evaporated, and the residue was partitioned between water (H₂ O)and ethyl acetate (EtOAc). The product was extracted into EtOAc (3×20ml). The extracts were combined, washed once with saturated sodiumbicarbonate, once with H₂ O, once with IM hydrochloric acid (HCI), oncewith H₂ O, and once with semi-saturated brine. After drying over Na₂SO₄, and filtration, the filtrate was evaporated in vacuo to afford thecrude product as a white solid. Recrystallization from cyclohexane andDCM gave t he pure amide as a white solid.

¹ H NMR (DMSO) δ 1.5-1.7 (m, 6H, CH₂ CH₂ CH₂ CH₂); 2.4 (m, 2H, CH₂ CH₂CH₂ CH₂); 6.6-6.7 (m, 3H, 2aryl, 1NH); 6.8 (broad singlet 1H, NH); 7.1(dd, 2H, aryl); 9.2 (s, 1H OH).

(c) 1- 4-(3,5-Difluoro-2-Nitrophenoxy)Phenyl!Cyclopentane-1-carboxamideand 1- 4-(3.5-Difluoro-4-Nitrophenoxy)Phenyl!Cyclopentane-1-carboxamide.

The product from Example 4(b) (0.55 g), in dry acetonitrile (ACN) (10ml), was treated at 0° C. under nitrogen with sodium hydride. Afterfifteen minutes, the mixture was warmed to RT and stirred for anotherhour. The white precipitate which ensued was taken up in a small amountof dimethylformamide (DMF), and then slowly added at 0° C. totrifluoronitrobenzene (0.52 g, Aldrich). The resulting mixture wasstirred at 0° C. for two hours, then at RT overnight. Solvent wasevaporated in vacuo, and the residue was partitioned between H₂ O andpet ether (40-60). The organic phase was separated, and the aqueousphase was extracted with EtOAc (3×12 ml). This was combined, washed withbrine, dried over sodium sulphate, filtered and evaporated in vacuo togive the crude product as a light yellow oil. Purification bychromatography (SiO₂) using EtOAc/cyclohexane (1:1) as the eluent gavethe title products as a yellow solid.

The products were obtained as a mixture of two isomers.

(d) 1- 4-(3.5-Difluoro-2-Aminophenoxy)Phenyl!Cyclopentane-1-Carboxamideand 1- (4-(3.5-Difluoro-4Aminophenoxy)Phenyl!Cyclopentane-1-Carboxamide.

The adduct from Example 4(c) (0.52 g) in ethanol (EtOH) (25 ml) wastreated with 10% palladium on activated charcoal (0.06 g), and thesuspension was hydrogenated at RT and atmospheric pressure for threehours. The catalyst was removed by filtration and the filtrate wasevaporated in vacuo to give a light brown oil.

The products were obtained as a mixture of two isomers.

(e) 1- 4-(3.5-Difluoro-2-Pivalamidophenoxy)Phenyl!Cyclopentane-1-Nitrile

A solution of the product from Example 4(d) (0.51 g) and triethylamine(0.17 g, Aldrich) in DCM was treated, dropwise, at 0° C., undernitrogen, with pivaloyl chloride. The reaction mixture was stirred at 0°C. for fifteen minutes, then at RT overnight.

DCM was evaporated, and the residue was taken up in water and extractedwith EtOAc (3×25 ml). The organic extracts were combined, washed oncewith saturated sodium bicarbonate, once with H₂ O and once withsemi-saturated brine. The organic phase was dried over Na₂ SO₄, filteredand evaporated under reduced pressure to afford the crude product as alight brown oil. Purification by chromatography (SiO₂) usingEtOAc/cyclohexane 1:3 as the eluent gave the product as an oil, whichwas crystallised from water and methanol to afford the title product asa white solid, mp 103°-5° C.

SYNTHETIC EXAMPLE 5 Preparation of N-{2,4-Difluoro-6-4-(2,6-Dioxo-4-Piperidinyl)Phenylethyl!Phenyl}- Pivalamide

(a) N-(2-Bromo-4-Difluorophenyl)Pivalamide

2-Bromo-4,6-difluoroaniline (50 g, Aldrich) in dry tetrahydrofuran (THF)(100 mi) was treated at 0° C., under nitrogen, with pivaloyl chloride(34.7 g), N-methylmorpholine (29.13 g, Aldrich) anddimethylaminopyridine (1.42 g, Aldrich). The mixture was warmed to roomtemperature, and was left stirring overnight. The THF was evaporatedunder reduced pressure, and the residue was taken up in water, washedthree times with ethyl acetate. The extracts were combined, washed oncewith 1N HC1, once with water, and once with brine. The organic solutionwas dried over sodium sulphate, filtered, and the filtrate wasevaporated in vacuo to afford the amide as a white solid.Recrystallization from ethyl acetate and cyclohexane gave the product asa white solid.

¹ H NMR (CDC1₃):δ1.35 (s,9H,C(CH₃)₃); 6.9-7.0(m,2H,NH and Ph); 7.2-7.3(m, 1H, aryl).

(b) N- 2.4-Difluoro-6-(Trimethylsilylethynyl)Phenyl!Pivalamide

A solution of the product from Example 5(a) (24.2 g) and(trimethylsilyl)acetylene (83 ml, Aldrich) in trimethylamine (TEA) (40ml) was degassed and placed under a nitrogen atmosphere. To thissolution was added copper (1) iodide (0.04 g, Aldrich) and tetrakis(triphenylphosphine) palladium (0.81 g). After stirring at roomtemperature for fifteen minutes, the reaction mixture was heated at60°-70° C. for five hours. On cooling, TEA was evaporated under reducedpressure, and the residue was partitioned between dichloromethane (DCM)and water. The DCM was separated , and the aqueous phase was extractedtwice with DCM. The organic extracts were combined, washed with brine,dried over sodium sulphate, filtered and evaporated in vacuo. The crudeproduct was purified by flash chromatograph (SiO₂), eluted withcyclohexane/ethylacetate 2:1. The product was obtained as a light brownsolid on evaporation of solvent.

¹ H NMR (CDCl₃):δ 0.3 (s,9H,SiC(CH₃)₃); 1.35 (s,9H C(CH₃)₃); 6.8-7.0 (m,2H,Ph); 7. 1 (broad s, 1H, NH)

(c) N-(2.4-Difluoro-6-Ethynylphenyl)Pivalamide

The product from Example 5(b) (20 g) in dry THF was treated undernitrogen with tetrabutylammonium fluoride solution 1M in THF (62 ml,Aldrich). The mixture was stirred at room temperature for 1 hour and THFwas evaporated under reduced pressure. The residue was partitionedbetween water and DCM, the organic phase was separated and the aqueousphase was extracted twice with DCM. The organic extracts were combined,washed once with brine, dried over sodium sulphate, filtered and thefiltrate was evaporated in vacuo to afford the crude product. Filtrationthrough silica gel using DCM as the eluent gave the title product as anoff white solid.

¹ H NMR (CDCl₃): δ 1.35 (s,9H,C(CH₃)₃); 3.4(s, 1H, CCH; 6.8-7.05 (m, 2H,Ph); 7.1 (broad s, 1H, NH)

(d) 3-(4-Bromophenyl) Glutaric acid

4-Bromobenzaldehyde (50.0 g, Aldrich), ethylacetoacetate (70.3 g,Aldrich), and piperidine (4.6 g, Fisons) were stirred togetherovernight. The resulting mixture was refluxed in the presence of ethanol(500 ml) and sodium methoxide (73.9 g) for 3-4 hours. On cooling, thesolvent was concentrated in vacuo, and the sodium salt, a yellow/orangesolid, was filtered, washed twice with diethyl ether and taken up inwater. Acidification with concentrated HCl gave a light yellow solid,which upon recrystallization from ethyl acetate gave the title productas an off white solid.

¹ H-NMR (DMSO): δ 2.4-2.7 (m, 4H, 2×CH₂ CH); 3.2-3.4 (m, 1H CH₂ CH);7.2-7.5 (dd, 4H aryl) 12.1 (broad s, 2H, 2×OH).

(e) 4-(4-Bromophenyl) Glutarimide

The product from Example 5(d) (20 g) was taken up in 0.88 ammoniasolution, then heated at 100° C. until all the ammonia solution hadevaporated. The resultant residue was heated at 200°-210° C. for 2-4hours until NH₃ evolution had ceased, (pH 5). On cooling, the reactionmixture was taken up in hot ethyl acetate from which the productcrystallized. This was removed by filtration, and the mother liquor wasconcentrated in vacuo from which the second crop (impure by thin layerchromatography) was obtained. This was filtered and dissolved in 0.88ammonia solution, and the reaction was repeated as above to afford thepure title product as a brown solid.

¹ H NMR (DMSO): δ 2.6-2.9 (m, 4H, 2×CH₂ CH); 3.4 (m, 1H CH₂ CH); 7.3-7.6(dd, aryl); 10.9 (s, 1H, NH).

(f) 4(4-Iodophenyl) Glutarimide

The product from Example 5(e) (1.9 g) in1,3-Dimethyl-3,4,5,6-tetrahydro-2-(1H) pyrimidione (50 ml, Aldrich) wastreated under nitrogen with copper iodide (6.8 g Aldrich) and potassiumiodide (17.7 g). The mixture was heated at ca. 160°-180° C. for 6-8hours. On cooling the reaction mixture was quenched with dilute HCl. Theaqueous phase was decanted and diluted with water. The dark brown sludgewas discarded, and the aqueous phase was washed three times with diethylether. The ethereal extracts were combined, washed once with brine,dried over sodium sulphate, filtered, and the filtrate was concentratedin vacuo. Trituration under cyclohexane gave the iodide as an off whitesolid.

Thin layer chromatography (SiO₂ ; Ethyl acetate/cyclohexane 1:1): R_(f)0.26.

(g) N-{2.4-Difluoro-6-2,6-Dioxo-4-Piperidinyl)Phenylethenyl!Phenyl}Pivalamide

The iodide from Example 5(f) (0.63 g) and the alkyne from Example 5(c)(0.53 g), in piperidine (8 ml, Fisons) were degassed and stirred at roomtemperature under nitrogen and then treated with tetrakis(triphenylphosphine) palladium (012 g, Aldrich). The reaction mixturewas stirred for one hour, and then quenched with saturated ammoniumchloride solution. The yellow solid which ensued was filtered, taken upin ethyl acetate, dried over sodium sulphate, filtered and evaporatedunder reduced pressure. Purification by flash chromatograph (SiO₂) withethylacetate cyclohexane 1:1 as the eluent gave the product as an offwhite solid. Recrystallization from water and methanol gave the productas a white solid, mp 114°-8° C.

Microanalysis: C₂₄ H₂₂ F₂ N₂ O₃ Calculated: C 67.91:H 5.22:N 6.6 Found:C 67.45:H 5.20:N 6.54.

SYNTHETIC EXAMPLE 6 Preparation of N-{2,4-Difluoro-6-4-(4-Methoxytetrahydropyran-4-yl)Phenylethenyl!- Phenyl}Pivalamide

(a) 4-(4-Bromophenyl)-4-Hydroxytetrahydropyran

1,4-Dibromobenzene (1 17.96 g, Aldrich) in tetrahydrofuran (THF) (700ml) was cooled to -7020 C. under nitrogen and butylithium (175 ml) wasadded dropwise. After stirring the mixture for 15 minutes,tetrahydro-4H-pyran4-one (25 g, Aldrich) in the THF (300 ml) was added.The reaction was left for 2 hours before being allowed to warm to roomtemperature. The reaction mixture was shaken with 5% citric acid (800ml), then extracted with diethyl ether (3×600 ml). The combined organiclayers were washed with water (500 ml), and dried over MgSO₄. Removal ofthe solvent from the filtrate gave the crude tide product as anoff-white solid.

(b) 4-(4-Bromophenyl)-4-Methoxytetrahydropyran

The product from Example 6(a) (64.28 g) in N,N-dimethylformamide (DMF)(400 ml) was added to ether washed sodium hydride (60% dispersion, 10.4g), the reaction mixture was then stirred under N₂ for 1 hour. Methyliodide (30.9 ml) in DMF was then added dropwise, and the reaction leftstirring overnight. On completion, the reaction was quenched with water(3000 ml) and extracted with ether (3×1000 ml). The combined organicextracts were washed with 2M HCL (1000 ml) and then water (1000 ml), anddried on MgSO₄. Removal of the solvent from the filtrate gave the crudetitle product as a red/orange oil which crystallised on standing.Purification by chromatography on silica gel, eluting with 40°-6020petroleum ether/diethyl ether (2:1) afforded the title product as awhite crystalline solid (30.18 g).

(c) 4-(4-Trimethylsilylethynylphenyl)-4-Methoxytetrahydropyran

The product from Example 6(b) (30 g), (trimethylsilyl) acetylene (12.8g), and piperidine (100 ml) were mixed together under nitrogen for 10minutes. Copper (I) iodide (0.13 g) and triphenylphosphine (0.18 g) werethen added followed by palladium (O) tetra(triphenylphosphine) (3×0.11g) with the exclusion of light. The reaction was heated for 4 hours at105° C., with the exclusion of light. On completion, the reactionmixture was poured into n-pentane (500 ml) and mixed with water (400ml). The separated aqueous layer was back extracted with n-pentane(500ml) and the combined organic phases were washed with a mixture of 2MHCl/saturated NH₄ Cl (400 ml:200 ml). The washed organic phase wassequentially washed with saturated NH₄ Cl (200 ml), water (600 ml), andbrine (600 ml) and finally dried over MgSO₄. Removal of the solvent fromthe filtrate in vacuo gave the crude tide product as a yellow/orange oil(31.52 g).

(d) 4-Ethynylphenyl)-4Methoxytetrahydropyran

The product from Example 6(c) (31.5 g) was dissolved in diethyl etherand stirred under nitrogen at 0° C. To this was added tetrabutylammoniumfluoride on silica (1.1 mmol F⁻ /g gel, Fluka) (100 g), and the reactionwas stirred for 2 hours at 0°. On completion, the reaction mire wasfiltered, washing the gel with excess diethyl ether. Removal of thesolvent from the filtrate gave the crude tide product as an orangeoil/gum. Purification by chromatography on silica gel, eluting withdichloromethane/diethyl ether (95:5) afforded the title product as apale yellow solid (18.01 g).

(e) N-(2-Bromo-4,6-Difluorophenyl) Pivalamide

2-Bromo-4,6-difluoroaniline (10.4 g, Aldrich) was dissolved indichloromethane (75 ml) and treated with pyridine (4.63 g) in an icebath. 4-Dimethylaminopyridine (0.61 g) was then added and the mixturewas allowed to warn to room temperature. After dropwise addition ofpivaloyl chloride (7.23 g, BDH), the reaction was stirred for 5 hours.On completion, the mixture was added to diethyl ether (250 ml), washedtwice with 2M HCI (250 ml) and the resulting organic layer was treatedwith saturated NaHCO₃ (2×250 ml). The organic layer was washed withwater (250 ml), and dried over MgSO₄. Removal of the solvent from thefiltrate gave the crude title product as a white solid (13.40 g).

(f) N-{2,4-Difluoro-6 Methoxytetrahydropyran-4-yl)Phenylethynyl!Phenyl}-Pivalamide

The product from Example 6(d) (15 g) and the product from Example 3(e)were dissolved in DMF (250 ml) with triethylamine (300ml) and stirredfor 20 minutes under N₂. To this solution, was added palladium (O)tetra(triphenylphosphine) (0.76 g), triphenylphosphine (0.29 g), andcopper (I) iodide (0.21 g), and stirring was continued for 20 minutes.The reaction was then heated to 100° C. for 8 hours. On completion, thereaction mixture was poured into water (3000 ml) and extractedsequentailly with hexan (2×600 ml), then diethyl ether (600 ml). Theether extract was treated with hexane to remove dissolved palladiumsalts, then the organic phases were combined, washed with aqueous citricacid and treated with 1/2 mole equivalent of triethylamine. The organiclayer was separated and washed with water (100 ml) and brine (1000 ml),before being dried on MgSO₄. Removal of the solvent in vacuo from thefiltrate gave the crude title product as a red/brown oil. Purificationby chromatography on silica, eluting with diethyl ether/40°-60°petroleum ether gave the title product as a white solid; mp 77°-79° C.

SYNTHETIC EXAMPLE 7 Preparation of N-{2,4-Difluoro-6-4-Tetrahydropyran-4-ylthio)Phenylethynyl!Phenyl}- Pivalamide

(a) 4-Tetrahydropyran-4-ylthio)Bromobenzene

4-Bromothiophenol (15.7 g, Lancaster) was treated with potassiumcarbonate (22.9 g) in dimethylformamide (DMF) (200 ml). This was stirredat room temperature for 1 hour. To this was added 4-chloropyran (10 g,Aldrich) dropwise followed by potassium iodide (approx. 2 g). Theresulting mixture heated to ˜700° C. and left stirring overnight.

The reaction mixture was poured into water (2000 ml) and extracted withdiethyl ether (3×300 ml). The organic layers were combined and washedwith water (2×250 ml) and then dried (MgSO4). After filtering andremoval of solvent in vacuo, a brown oil was obtained which was purifiedon silica (Merck) eluting with diethyl ether: 40/60 petrol (1:1) to givethe title product as a yellow crystalline solid (18.91 g).

(b) 4-(Tetrahydropyran-4-ylthio)Phenylacetylene

The product from Example 7(a) (4.0 g) was mixed withtrimethylsilylacetylene (1.76 g, Aldrich) and piperidene (12 ml) underN₂ for 10 minutes. Added to this were the catalysts copper iodide (17mg, Aldrich),triphenylphosphine (23 mg, Aldrich) andtetrakistriphenylphosphine palladium (o) (15 mg, Aldrich). Two furtheradditions of the later catalyst were made at 20 minute intervals (2×15mg). All such additions as well as the reaction were carried out withthe exclusion of light. Reaction was heated to 105° C. for 5 hours. Oncompletion the reaction was poured into diethyl ether (150 ml) and mixedwith water (200 ml). The organic phase was removed while the aqueous wasextracted with diethyl ether (2×150 ml). The organics were combined andwashed with a 2:1% mix of 2M HCl/NH₄ Cl (100:50 ml) and separated. Theorganics were then washed with water (100 ml),brine(100 ml) and thendried (MgSO₄). The solvent was removed in vacuo to give a brown oil.

This oil (4.35 g) was dissolved in dry diethyl ether (120 ml)-andstirred under anhydrous N₂ at 0° C. To this was addedtetrabutylammoniumfluoride (TBAF) on silica gel (13.3 g, Fluka) and thereaction stirred at this temperature for 2 hours. On completion,the TBAFwas filtered off and washed with dry diethyl ether and the filtrateconcentrated in vacuo to give an orange oil. Purification was achievedby chromatography on silica eluting with diethyl ether: 40/60 petrol(1:2) to give the tide compound as a pale yellow solid (2.5 g)

Microanalysis: C₁₃ H₁₅ OS % found (calculated) C 77.88 (79.19), H 6-63(6.89).

(c) N-{2,4-Difluoro-6-4-(Tetrahydropyran-4-ylthio)Phenylethynyl!Phenyl}- Pivalamide

The product from Example 6(e) (1.27 g) and the product from Example 7(b)(1.0 g) were mixed with NEt₃ (20 ml) and DMF (15 ml) and stirred underN₂. To this were added the catalysts tetrakistriphenylphosphinepalladium (O) (50 mg), triphenylphosphine (17.5 mg) and copper iodide(13.1 mg) and the solution stirred for 20 minutes. The reaction was thenheated to 100° C. for 2 hours. On completion the mixture was poured intowater (150 ml), extracted with diethyl ether (3×150 ml). The organicphases were combined and washed with aqueous citric acid (0.5 mole equ.of NEt₃). The organic layer was removed and washed with water (100 ml)be fore being dried (MgSO₄), filtered and the solvent removed in vacuoto give a brown oil. Purification was by chromatography on silicaeluting with diethyl ether: 40/60 petrol (2:1) to afford the titlecompound as a yellow solid (350 mg) ; mp 148°-149° C.

SYNTHETIC EXAMPLE 8 Preparation of N-{6-4-(1-Carbamoyl-1-Methylethoxy)Phenylethynyl!2,4-Difluoro-Phenyl}Pivalamide

(a) Ethyl 2-(4-Iodophenoxy-2-Methylpropanoate

Sodium ethoxide was prepared by disposing sodium metal (0.63 g) inabsolute ethanol (60 ml) at room temperature. To this solution was added4-iodophenol (6.0 g, Aldrich) and ethyl 2-bromo-2-methylpropanoate (5.6g, Aldrich) and the mixture heated to reflux for 6 h.

On completion, the mixture was poured into water (100 ml), 1M NaOH (150ml) and ethyl acetate (200 ml). The organic layer was quickly removedand washed with 2M HCI (150 ml) followed by sodium bicarbonate (100 ml)and water (100 ml) before being dried (MgSO₄). After filtering thesolvent was removed in vacuo to give a yellow oil which was purified onsilica gel eluting with diethyl ether: 40/60 petrol (1:2) to afford thetide product as a colourless oil (5.60 g).

(b) Ethyl 2- 4-(3,5-Difluoro-2-Pivalamidophenylethynyl)Phenoxy!-2-Methylpropanoate

The product from Example 5(c) (0.04 g) and the product from Example 8(a)(0.56 g) together with triethylamine (10 ml) and dimethylformamide (0.5ml) were stirred together under N₂ at room temperature. With thereaction flask completely excluded from light, the catalysts CuI (3 mg,Aldrich) and bis(triphenyl phosphine) palladium (II) chloride (24 mg.Aldrich) were added and the reaction stirred at room temperature for 3h.

On completion, the triethylamine was removed in vacuo and the residuetaken up in diethyl ether (200 ml), before being washed with water (200ml), the two layers were separated and the aqueous re-extracted withethyl acetate (150 ml). The combined organics were washed with 5% citricacid (150 ml) and water (150 ml) before being dried (MgSO₄). Afterfiltering the solvent was removed in vacuo to give the brown oily solidwhich was purified on silica gel eluting with diethyl ether: 40/60petrol (1:1) to afford the title product as a yellow oil (0.62 g).

(c) 2- 4-(3,5-Difluoro-2-Pivalamidophenylethynyl)Phenoxy!-2-methylpropanoic acid

The product from Example 8(b) (together with a quantity of an earlierbatch) (Total=0.92 g) was dissolved up in methanol with stirring at roomtemperature. To this was added NaOH (100 mg) in water (15 ml) dropwise.The reaction mixture was then refluxed from 5 h.

On completion, the solvent was removed in vacuo and the aqeuous layeracidified to pH=1 with 2M HCl The resulting solid was extracted intoether (100 ml) and dried (MgSO₄). In order to remove an impurity thatstill remained, the solid was extracted into 1M NaOH and washed withdiethyl ether (100 ml). This basic To was reacidified with 2M HCl, theproduct extracted into diethyl ether (100 ml) and dried (MgSO₄). Afterfiltering, the solvent was removed in vacuo to give the title product asthe crude yellow oil (0.84 g).

(d) N-{6-4-(1-Carbamoyl-1-Methylethoxy)Phenylethynyl!-2,4-Difluorophenyl}-Pivalamide

The product from Example 8(c) was dissolved up in tetrahydrofuran (30ml) and triethylamine (0.28 ml, Aldrich) and then cooled in an ice bath.To this was added methylchloroformate (0.2 g, Aldrich) rapidly withcontinuous stirring. After 1 h, anhydrous NH₃ was passed through thesolution for approx. 5 min. The mixture was then removed from thecooling bath, stirred at room temperature for 1 h. and then leftstanding overnight.

On completion, the tetrahydrofuran and triethylamine were removed invacuo and the residue taken up in dichloromethane (200 ml). This waswashed with 5% citric acid (150 ml) and then this layer re-extractedwith dichloromethane (200 ml). The combined organic layers were washedsuccessively with sodium bicarbonate (100 ml) and water (100 ml) beforebeing dried (MgSO₄). After filtering the solvent was removed in vacuo togive a pale yellow oil which was triturated with 40/60 petroleum etherto give a pale yellow solid. Purification was achieved on silica gel 60(Merck) eluting with diethyl ether to afford the title compound as awhite solid (0.62 g) ; m.p. 89°-90° C.

₁ H-NMR (CDCl₃) δ:7.45 (m,2H ArH), 7.15 (s, 1H, NH), 7.05 (m, 1H, ArH),6.95 (m, 2H, ArH), 6.50 & 5.40 (s, 2H, NH₂), 1.60 (s, 6H, methyl-H),1.35 (s, 9H ^(t) Bu).

SYNTHETIC EXAMPLE 9 Preparation of N-{6-4-(1-Carbamoyl-1-Methylethyl)Phenylethynyl!2,4-Difluoro-Phenyl}Pivalamide

(a) Ethyl (4-Bromophenyl)Ethanoate.

4-Bromophenylacetic acid (45 g, Aldrich) was dissolved up in ethanol(300 ml) at room temperature along with p-toluenesulphonic acid (0.75g). The reaction mixture was then stirred overnight.

The ethanol was then removed in vacuo and the residue taken up indiethyl ether (200 ml). The diethyl ether layer was then washed withwater (200 ml) and the aqueous layer re-extracted with diethyl ether(200 ml). The combined organics were then dried (MgSO₄), filtered andthe solvent removed in vacuo to give the title product as a pale yellowoil (50.27 g).

(b) Ethyl 2-(4-Bromophenyl)-2-Methylpropanoate.

NaH (60% dispersion in mineral oil) (33.12 g, Aldrich ) was washed withdry diethyl ether before being formed into a slurry with ethylene glycoldiethyl ether (200 ml). To this was added the product from Example 9(a)(50.25 g) and methyl iodide (51.5 ml Aldrich) dropwise in more ethyleneglycol dimethyl ether (150 ml). This was then left to reflux overnightunder N₂.

The ethylene glycol dimethyl ether was then removed by distillation atreduced pressure. The resulting solid was then cooled in an ice bath anddiethyl ether (400ml) was added. After stirring, water (300 ml) wasadded, stirred again and then the two layers separated.

The diethyl ether layer was extracted with water (2×300 ml) before beingdried (MgSO₄). After filtering the solvent was removed in vacuo to givea yellow oil which was purified by distillation to give the titleproduct as a colourless oil (35.5 g) ; b.pt. 84°-860° C. at 0.2 mm/Hg.

(c) Ethyl 2-(4-Iodophenyl)-2-Methylpropanoate.

The product from Example 9(b) (35.5 g), nickel bromide (0.81 g, Aldrich)and potassium iodide (109 g) were stirred together in dimethylformamide(DMF) (250 ml) under N₂ before tributyl phosphine (3.3 ml, Aldrich) wasadded at room temperature. The reaction was then heated to reflux for 18h.

The reaction mixture was allowed to cool to room temperature and addedto water (1200 ml) before being extracted into ethyl acetate (500 ml).The layers were separated and the aqueous re-extracted with ethylacetate (2×400 ml). The organics were combined and washed with 2M HCl(400 ml) and saturated sodium sulphite solution (200 ml) before beingdried (MgSO₄). After filtration the solvent was removed in vacuo to givethe title product as a pale yellow oil (40.10 g).

(d) Ethyl 2- 4-(3,5 Difluoro-2-Pivalamidophenylethynyl)Phenyl!-2-MethylPropanoate.

The product from Example 5(c) (12.1 lg) and the product from Example9(c) (12.0 g) were stirred together in triethylamine (120 ml, Aldrich)and dimethylformamide (25 ml) under N₂ (free of O₂ by passage throughFieser's solution). The mixture was stirred at room temperature with N₂bubbled through the solution until all the solids had dissolved. Withthe reaction flask completely excluded from light,bis(triphenylphosphine)palladium(II) chloride (0.76 g, Aldrich) andcopper iodide (0.36 g, Aldrich) were added and the reaction stirred atroom temperature for 24 h.

On completion, triethylamine was removed in vacuo and the residuepartitioned between saturated ammonium chloride (350 ml) and ethylacetate (400 ml). The organics were separated and washed with 2M HCl(250 ml), 20% sodium thiosulphate solution (250 ml) and brine (250 ml).The organic layer was then dried (MgSO₄), filtered and the solventremoved in vacuo to give a brown oil which was purified on silica gel,eluting with diethyl ether : 40/60 petrol ether (1:1) to afford thetitle product as a yellow solid (10.10 g).

(e) 2- 4-(3,5-Difluoro-2-Pivalamidophenylethynyl)Phenyl!-2-MethylPropanoic Acid

The product from Example 9(d) (10.1 g) was dissolved in methanol (100ml) at room temperature. To this was added NaOH (1.10 g) in water (100ml) dropwise with rapid stirring. The reaction mixture was then refluxedfor 5 h. before being stirred at room temperature overnight.

On completion of reaction, the solvent was removed in vacuo and theresulting aqueous layer, first washed with diethyl ether (250 ml) andthen acidified to pH=1 with 2M HCl. The solidified product was extractedinto diethyl ether (300 ml), which was dried (MgSO₄), then filtered andthe solvent removed in vacuo to give the crude title product as a paleyellow solid (7.8 g)

(f) N-{6-4-(1-Carbamoyl-1-Methylethyl)Phenylethynyl!-2,4-Difluorophenyl}Pivalamide:

The product from Example 9(e) was dissolved in tetrahydrofuran (150 ml)and triethylamine (2.8 ml, Aldrich) and then cooled in an ice bath. Tothis was added methylchloroformate (1.89 g, Aldrich) rapidly withcontinuous stirring. After 1 h., anhydrous NH₃ was passed through thesolution for approx. 15 min. The mixture was then removed from thecooling bath, stirred at room temperature for 1 h and then left standingovernight.

On completion, the tetrahydrofuran and triethylamine were removed invacuo and the residue taken up in ethyl acetate (350 ml). This waswashed successively with 5% citric acid (250 ml), sodium bicarbonate(250 ml) and water (250 ml) before being dried (NaSO₄). After filtrationthe solvent was removed in vacuo to give a pale yellow oil which wasrecrystallised from ethyl acetate and 40/60 petroleum ether to affordthe title compound as a white solid (4.51 g); m.p. 170°-172° C.

SYNTHETIC EXAMPLE 10 Preparation of Trans-N-(2,4-Difluoro-6-{2-4-(4-Methoxytetrahydropyran-4-yl)Phenyl!- ethenyl}Phenyl)Pivalamide

The product from Example 6 (3.0 g) was dissolved in dimethylsulphoxideand Pd(dba)₂ (200 mg) was added. The mixture was treated with H₂ atatmospheric pressure until gas uptake ceased. On completion, thereaction was added to water (500 ml) and extracted with ethyl acetate(2×400 ml). The combined organic extracts were washed with water (2×300ml) and then dried on MgSO₄, and filtered. Removal of the solvent invacuo gave a yellow oil which was dissolved in diethyl ether, treatedwith charcoal, then filtered through, Hyflo. Removal of the solvent fromthe filtrate gave the crude title product. Precipitation from ethylacetate/40°-60° petroleum ether afforded the title product as a whitesolid; mp 150°-151° C.

SYNTHETIC EXAMPLE 11 Preparation of N-(2,4Difluoro-6-{2-4(4-Methoxytetrahydropyran-4-yl)Phenyl!Ethyl}- Phenyl)Pivalamide

To a solution of the product from Example 6 (3.0 g) in ethanol, wasadded 10% palladium on charcoal (300 mg). The reaction mixture wastreated with H₂ at atmospheric pressure until uptake ceased. Oncompletion, the reaction was filtered and the solvent was removed fromthe filtrate in vacuo to give a green oil. Traces of remaining catalystwere removed by filtration to give a yellow oil. The oil wasprecipitated from ethyl acetate/40°-60° petroleum ether to afford thetitle compound as a white solid, mp 147°-148°C.

SYNTHETIC EXAMPLES 12-69

The following compounds of formula (I) were prepared in a manneranalogous to the methods of Synthetic Examples 1 to 4.

12) N- 2-Fluoro-6-(4-trans-cyclohexylsulfamoylphenoxy)phenyl!pivalamide,mp 176°-178° C.;

13) N- 2-Fluoro-6-(3-trifluoromethoxyphenoxy)phenyl!pivalamide, mp84°-85° C.;

14) N-{2,4-Difluoro-6-4-(4-methoxytetrahydropyran-4-yl)phenoxy!phenyl}pivalamide, mp 145°-146°C.;

15) 2- 4-(3,5-Difluoro-2-pivalamidophenoxy)phenyl!-2-methylpropanoicacid, mp 168°-170° C.;

16) Methyl 2- 4-(3,5-difluoro-2-pivalamidophenoxy)phenyl!-2-methylpropanoate, mp 103°4° C.;

17) 1- 4-(3-Fluoro-2-pivalamidophenoxy)phenyl!cyclopentane-1-carboxylicacid, mp 152°-4° C.;

18) 1-4-(3-Fluoro-2-pivalamidophenoxy)phenyl!cyclopentane-1-carboxamide, mp175°-60° C.;

19) N- 2,4-Difluoro-6-(4-piperidinylcarbonylphenoxy)phenyl!pivalamidehemihydrate, mp 55°6° C.;

20) N-{2-Fluoro-6- 4-phenylsulfamoyl)phenoxy!phenyl}pivalamide, mp179°-181° C.;

21) N-{2-Fluoro-6- 4-(N-tert-butylsulfamoyl)phenoxy!phenyl}pivalamide,mp 197°-199° C.;

22) 2,4-difluoro-6- 4-(4-morpholinocarbonyl)phenoxyl!phenylpivalamide,mp 63°-65° C.;

23) 2,2-Dimethyl-N-{2,4-difluoro-6-4-(2,6-dioxopiperidin-4yl)phenoxy!phenyl}butanamide, 0.8 hydrate, mp180°-1° C.;

24) N-{2-Fluoro-6- 4-(1-imidazolyl)phenoxy!phenyl}pivalamide, mp 207°-9°C.;

25) N-{2,4-Difluoro-6- 3-fluoro-5-(4-methoxy-4-pyranyl)phenoxy!phenyl}-pivalamide, mp 102°-103° C.

26) N- 2-(4-Chlorophenoxy)-6-fluorophenyl!pivalamide, mp 145°-6° C.;

27) N-{2- 4-(2,2-Diethoxyethoxy)phenoxy!-6-fluorophenyl}pivalamide, mp63°-5° C.;

28) N-{2-Fluoro-6- 4-(2,2-dimethoxyethoxy)phenoxy!phenyl}pivalamide, mp86°-7° C.;

29) N-{2-Fluoro-6- 4-(2-methoxyethoxymethoxy)phenoxy!phenyl}pivalamide,Microanalysis C₂₁ H₂₆ FNO₅ : C 64.56 (64.45), H 6.84 (6.65), N 3.41(3.58);

30) 4-(3-Fluoro-2-pivalamidophenoxy)phenyl-1-methylethanesulphonate, mp130°-2° C.;

31) 4-(3-Fluoro-2-pivalamidophenoxy)phenylpivalate, mp 121°-123° C.;

32) N- 2-Fluoro-6-(4methylphenoxy)phenyl!pivalamide, mp 115°-6° C.;

33) N- 2-(4-Chlorophenoxy)-6-fluorophenyl!cyclopentanecarboxamide, mp130°-1° C.;

34) N- 2-Fluoro-6-(4-methoxyphenoxy)phenyl!pivalamide;

35) 4-(3,5-Difluoro-4-pivalamidophenoxy)phenyl!piperidin-2,6-dione, mp177°-178° C.;

36) Ethyl 4-(3,5-difluoro-2-pivalamidophenoxy)benzoate, mp 110°-112° C.;

37) N-tert-Butyl-N'-{4- (2-pivalamido)3-fluorophenoxy!phenyl}urea, mp176°-178° C.;

38) N-{2-fluoro-6-4-(2,6-dimethyoxybenzoylamino)phenoxy!phenyl}pivalamide, mp 194°-196°C.;

39) N- 2-Fluoro-6-(4-pivalamidophenoxy)phenyl!pivalamide, mp 187°-189°C.;

40) N- 2-Fluoro-6-(4-phenylsulphonylaminophenoxy)phenyl!pivalamide, mp237°-240° C.;

41) N-{2-Fluoro-6- 4-benzamidophenoxy!phenyl}pivalamide, mp 264°-267°C.:

42) N-{2- 4(Isopropylsulfonyl)phenoxy!-6-fluorophenyl}pivalamide, mp153°-154° C.;

43) N-{2-Fluoro-6- 4-(isopropylsulfinyl)phenoxy!phenyl}pivalamide, mp155°-156° C.;

44) N- 2-Fluoro-6-(4-tert-butoxycarbonylaminophenoxy)pivalamide, mp209°-214° C.;

45) N- 2-Fluoro-6-(4-trifluorophenoxy)phenyl!pivalamide, mp 155° C.;

46) N-{2-4-(2,2-Dimethyoxyethyl)phenoxy!-3-trifluoromethylphenyl}pivalamide;

47) 3- 2-(4-Chlorophenoxy)-6-fluorophenyl!-1,1-dimethylurea, mp 143°-40°C.;

48) N- 2-(4-Chlorophenoxy)phenyl!pivalamide, mp 90°-1° C.;

The following compounds of formula (I) were prepared in a manneranalogous to the methods of Synthetic Examples 5 to 9.

49) N-2,4-Difluoro-6-{3-chloro-4-(2,6-dioxo-4-piperidyl)phenyl!ethynyl}- phenyl)pivalamide, mp178°-180° C.;

50) N-{2,4-Difluoro-6- 4-(3-methoxy-8-oxa- 3.2.1!-bicyclooctan-3-yl)phenyl- ethynyl!phenyl}pivalamide, mp 64°-68° C.;

51) N-{2,4-Difluoro-6-4-(4-hydroxytetrahydropyran-4-yl)phenylethynyl!phenyl}- pivalamide, mp85°-91° C.;

52) 1- 4-(3,5-Difluoro-2-pivalamidophenylethynyl)phenyl!cyclopentane-1-carboxamide hydrate, mp 195°-7° C.;

53) Methyl 2-{4-3,5-difluoro-2-(2,2-dimethylpropanamido)phenyl!ethynyl}phenyl-2- methylpropanoate, mp 71°-30° C.;

54) N-{2,4-Difluoro-6- 4-(tetrahydropyran-4-ylsulphony)phenylethynyl!phenyl}pivalamide, mp 255°-6° C.;

55) N-{2,4-Difluoro-6-4-(tetrahydropyran-4-yl)phenylethynyl!phenyl}propanamide, mp 173°-5° C.;

56) N-{2,4-Difluoro-6-4-(4-methoxyethoxymethoxytetrahydropyran-4-yl)phenyl-ethynyl!phenyl}pivalamide, mp 96°-97° C.;

57) 2,4-Difluoro-6-{ 3-(4-methoxytetrahydropyran)phenyl!ethynyl}-pivalamide;

58) N-{2,4-Difluoro-6-4-(5,6-dihydro-2H-pyran-4-yl)phenylethynyl!phenyl}- pivalamide, mp165°-167° C.;

59) 4,6Difluoro-2-4-(1,3,6-trioxaheptyl)phenylethynyl)phenyl!pivalamide, mp 86°-8° C.;

60) 3-4-(3,5-Difluoro-2-Pivalamidophenylethynyl)phenyl!-N,N-pentamethylene-pentadiamide, 0.5 hydrate, mp 90° C. (softens);

61) N-{2,4Difluoro-6-2-(4-hydroxy-3,5-dimethylphenyl)ethyl!phenyl}isobutyramide, mp 140°-141°C.;

62) N-{2,4-Difluoro-6- 2(4-isopropylsulphonyloxy)ethyl!phenyl}mp 111°-2°C.;

63) N-{2,4-Difluoro-6-2-(4-hydroxy-3,5-dimethylphenyl)ethyl!phenyl}isobutyramide, mp 187°-188°C.;

64) 2-{4-3,5-Difluoro-2-(2,2-dimethylpropanamido)phenyl!ethynyl}phenyl-2-methylpropanoic acid, mp 110°-111° C.;

The following compounds of formula (I) were prepared using the processesdescribed above.

65) N- 2-(4-Chlorobenzyloxy)-4,6-difluorophenyl!pivalamide, mp 98°-9°C.;

66) (+-)-N-{2-Fluoro-6- 1-(4-chlorophenyl)ethoxy!phenyl}pivalamide, mp110°-111° C.;

67) N-{2-Fluoro-6- 4-(2,2-dimethoxyethoxy)phenylthio!phenyl}pivalamide;

68) N- 2-Fluoro-6-(4-methoxyphenylsulfonyl)phenyl!pivalamide, mp179°-181 ° C.;

69) N- 2-Fluoro-6-(4-methoxyphenylthio)phenyl!pivalamide, mp 101°-103°C.;

PHARMACEUTICAL FORMULATION EXAMPLES

In the following Examples, the "active ingredient" is as hereinbeforedefined, preferably one of the compounds of Synthetic Examples 1 to 69.

    ______________________________________                                        Tablet                                                                                          Per tablet                                                  ______________________________________                                        Active Ingredient (sub 250 μm)                                                                 5.0 mg                                                    Lactose             82.0 mg                                                   Starch              10.0 mg                                                   Povidone            2.0 mg                                                    Magnesium Stearate  1.0 mg                                                    ______________________________________                                    

Mix together the active ingredient, lactose and starch. Granulate thepowders using a solution of povidone in purified water. Dry thegranules, add the magnesium stearate and compress to produce 100 mgtablets.

    ______________________________________                                        Controlled release tablet                                                                       Per tablet                                                  ______________________________________                                        Active ingredient (sub 250 μm)                                                                 500 mg                                                    Hydroxypropylmethylcellulose                                                                      112 mg                                                    (Methocel K4M Premium)                                                        Lactose B.P.        53 mg                                                     Povidone B.P.C.     28 mg                                                     Magnesium Stearate  7 mg                                                                          700 mg                                                    ______________________________________                                    

The formulation may be prepared by wet granulation of the first threeingredients with the solution of povidone, followed by addition of themagnesium stearate and compression.

    ______________________________________                                        Capsule                                                                                        Per capsule                                                  ______________________________________                                        Active ingredient (sub 250 μm)                                                                250 mg                                                     Lactose B.P.       143 mg                                                     Sodium Starch Glycollate                                                                         25 mg                                                      Magnesium Stearate 2 mg                                                                          420 mg                                                     ______________________________________                                    

Capsules may be prepared by admixing the ingredients of the formulationand filling two-part hard gelatin capsules with the resulting mixture.

    ______________________________________                                        Controlled release capsule                                                                    Per capsule                                                   ______________________________________                                        Active ingredient 250 mg                                                      Microcrystalline Cellulose                                                                      125 mg                                                      Lactose BP        125 mg                                                      Ethyl Cellulose   13 mg                                                                         513 mg                                                      ______________________________________                                    

The controlled-release capsule formulation may be prepared by extrudinga mixture of the first three ingredients, then spheronising and dryingthe extrudate. The dried pellets are coated with the ethyl cellulose asa controlled-release membrane and filled into two-part hard gelatincapsules.

    ______________________________________                                        Powder capsule for inhalation                                                                    Per capsule                                                ______________________________________                                        Active Ingredient (0.5-5.0 μm powder)                                                           4.0 mg                                                   Lactose (30-90 μm powder)                                                                       46.0 mg                                                  ______________________________________                                    

The powders were mixed until homogeneous and filled into suitably sizedhard gelatin capsules (SOmg per capsule).

    ______________________________________                                        Injectable solution                                                           Active Ingredient                                                                             10.0         mg                                               Water for Injections B.P.                                                                     to 1.0       ml                                               ______________________________________                                    

The active ingredient was dissolved in half of the Water for Injectionsand then made up to volume and sterilised by filtration. The resultingsolution was distributed into ampoules under aseptic conditions.

    ______________________________________                                        Intramuscular injection formulation                                           Active ingredient                                                                           0.20           g                                                Benzyl Alcohol                                                                              0.10           g                                                Glycofurol 75 1.45           g                                                Water for Injection                                                                         q.s. to 3.00   ml                                               ______________________________________                                    

The active ingredient is dissolved in the glycofurol. The benzyl alcoholis added and dissolved, then water added to 3 ml. The solution isfiltered through a sterile micropore filter and sealed in sterile 3 mlglass vials.

    ______________________________________                                        Inhalation aerosol                                                            Active Ingredient (0.5-5.0 μm powder)                                                           200        mg                                            Sorbitan Trioleate   100        mg                                            Saccharin Sodium (0.5-7.0 μm powder)                                                            5          mg                                            Menthol              2          mg                                            Trichlorofluoromethane                                                                             4.2        g                                             Dichlorodifluoromethane                                                                            to 10.0    ml                                            ______________________________________                                    

The sorbitan trioleate and menthol were dissolved in thetrichloro-fluoromethane. The saccharin sodium and active ingredient weredispersed in the mixture which was then transferred to a suitableaerosol canister and the dichlorofluoromethane injected through thevalve system. This composition provides 2 mg of active ingredient ineach 100 μl dose.

    ______________________________________                                        Syrup formulation                                                             Active ingredient                                                                           0.25           g                                                Sorbitol Solution                                                                           1.50           g                                                Glycerol      1.00           g                                                Sodium Benzoate                                                                             0.0050         g                                                Flavour       0.0125         ml                                               Purified Water                                                                              q.s. to 5.0    ml                                               ______________________________________                                    

The sodium benzoate is dissolved in a portion of the purified water andthe sorbitol solution added. The active ingredient is added anddissolved. The resulting solution is mixed with the glycerol and thenmade up to the required volume with the purified water.

    ______________________________________                                        Suppository formulation                                                                             Per suppository                                         ______________________________________                                        Active ingredient (63 μm)*                                                                         250 mg                                                Hard Fat, BP (Witepsol H15 - Dynamit Nobel)                                                           1770 mg                                                                       2020 mg                                               ______________________________________                                         *The active ingredient is used as a powder wherein at least 90% of the        particles are of 63 μm diameter or less.                              

One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at amaximum temperature of 45° C. The active ingredient is sifted through a200μm sieve and added to the molten base with mixing, using a Silversonfitted with a cutting head, until a smooth dispersion is achieved.Maintaining the mixture at 45° C., the remaining Witepsol H15 is addedto the suspension which is stirred until homogenous. The entiresuspension is then passed through a 250 μm stainless steel screen and,with continuous stirring, allowed to cool to 40° C. At a temperature of38°-40° C., 2.0 μg aliquots of the mixture are filled into suitableplastic moulds and the suppositories allowed to cool to roomtemperature.

    ______________________________________                                        Pessary formulation                                                                           Per pessary                                                   ______________________________________                                        Active ingredient (63 μm)                                                                    250 mg                                                      Anhydrous Dextrose                                                                              380 mg                                                      Potato Starch     363 mg                                                      Magnesium Stearate                                                                              7 mg                                                                          1000 mg                                                     ______________________________________                                    

The ingredients are mixed directly and pessaries prepared by compressionof the resulting mixture.

Biological Assay

In Vitro Inhibition of ACAT

The in vitro esterification of cholesterol in the presence of ACAT andthe test compound was assayed radiometrically using ¹⁴ C!oleoyl CoA assubstrate:

    .sup.14 C!oleoyl CoA+cholesterol→ .sup.14 C!oleoyl cholesterol+CoASH

The enzyme is membrane-associated in vivo. Microsomal protein istherefore used as the source of both ACAT and cholesterol. The compoundsof the invention were tested against enzyme derived from human embryo407 intestinal epithelial cell line.

¹⁴ C!Oleoyl CoA was incubated with microsomal protein at 37° C., pH 70,in the presence of various concentrations of the test compound. After 4minutes, the reaction was stopped by the addition of ice-coldchloroform/methanol containing a known amount of ³ H!oleoyl cholesterolto compensate for the loss of any ¹⁴ C! product. A known volume of theresulting lower phase, which contains lipidic material from thereaction, was dried, redissolved in hexane containing unlabelled oleoylcholesterol (TLC marker) and run on a quantitative TLC plate (silicagel). The oleoyl cholesterol spot was visualised (iodine vapour),removed from the TLC plate and its radioactivity measured byscintillation counting.

A plot of ACAT inhibitory activity vs concentration was prepared foreach test compound and the corresponding IC₅₀ determined. The compoundsof Synthetic Examples 1 to 69 were all found to significantly inhibitACAT. For example, the compounds of Examples 1 to 10 were all found tohave an IC₅₀ of less than 10 μM.

We claim:
 1. A compound of formula (I) ##STR5## or a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof, wherein:W is hydrogen, or a C₁₋₁₂ hydrocarbyl group optionallysubstituted by one or more groups independently selected from halo, C₁₋₄alkyl, C₁₋₄ alkoxy, hydroxy, C₁₋₄ haloalkyl C₁₋₄ haloalkoxy, and RC(O)--(wherein R is selected from hydrogen, C₁₋₄ alkyl C₁₋₄ alkoxy, hydroxy,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy); X is --NR¹ C(O)NR² --, --NR¹C(O)--, --NR¹ C(O)O--, --C(O)NR² --, or --OC(O)NR² -- (wherein R¹ and R²are independently selected from hydrogen, C₁₋₄ alkyl, and Y is a bond,C₂₋₄ alkynylene, C₂₋₄ alkenylene (cis or trans), C₁₋₄ alkylene,--(CH₂)_(n) --O--(CH₂)_(p) --, or --(CH₂)_(n) S(O)_(q) --(CH₂)_(p) --,(wherein n and p are integers independently selected from 0, 1, 2, 3,and 4; providing that n+p is not greater than 4; and q is an integerselected from 0, 1, and 2), and Y is optionally substituted by one ormore groups independently selected from halo, C₁₋₄ alkyl, and C₁₋₄haloalkyl; E is a bond, C₁₋₄ alkylene, --(CH₂)_(r) O--(CH₂)_(s) --,--(CH₂)_(r) --S(O)_(t) --(CH₂)_(s) --, --(CH₂)_(r) C(O)--(CH₂)_(s) --(wherein r and s are integers independently selected from 0, 1, 2, 3 and4; providing that r+s is not greater than 4; and t is an integerselected from 0, 1, and 2), --OC(O)--, --C(O)O--, --S(O)₂ N(R³)--,--(R³)NS(O)₂ --, --C(O)N(R³)--, --(R³)NC(O)N(R⁴)--, or --(R³)NC(O)--(wherein R³ and R⁴ are independently selected from hydrogen, C₁₋₄ alkyl,and C₁₋₄ haloalkyl); Z is an aliphatic heterocyclic ring system, and Zis optionally substituted by one or more groups independently selectedfrom halo, cyano, --CO₂ R⁶, --C(O)NR⁶ R⁷, --NR⁶ R⁷ (wherein R⁶ and R⁷are independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₄haloalkyl), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,hydroxy, and C₂₋₈ polyether, phenyl rings A and B are optionallysubstituted by one or more groups independently selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, hydroxy, cyano, R⁸R⁹ NC(O)--, R⁸ C(O)N(R⁹)--, R⁸ C(O)O--, and R⁸ C(O)-- (wherein R⁸ and R⁹are independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₄haloalkyl).
 2. A compound of formula (I) according to claim 1 wherein:Wis C₃₋₇ alkyl optionally substituted as described in claim 1; X is--C(O)NR² --, --NR¹ C(O)--, or --NR¹ C(O)NR² -- (wherein R¹ and R² areas defined in claim 1; Y is ethylene, ethenylene, ethenylene, --O--,--S--, --CH₂ O--, or --OCH₂ --; E is --O--, --OCH₂ --, --CH₂ O--, abond, --C(O)N(R³)--, --(R³)NC(O)--, --S--, --S(O)--, --S(O)₂ --,--R³)NS(O)₂ --, --S(O)₂ N(R³)--, --(R³)NC(O)N(R⁴)--, or --C(O)--(wherein R³ and R⁴ are as defined in claim 1); and Z is a 5-- or6-membered saturated heterocyclic ring and Z is optionally substitutedas described in claim 1;or a salt, solvate, or physiologicallyfunctional derivative thereof.
 3. A compound of formula (I) according toclaim 1 selected from:N-{2,4-Difluoro-6-4-(2,6-dioxo-4-piperidinyl)phenylethynyl!phenyl}pivalamide;N-{2,4-Difluoro-6-4-(4-methoxytetrahydropyran-4-yl)phenylethynyl!phenyl}- pivalamide;N-{2,4-Difluoro-6-4-(2,6-dioxo-4-piperidinyl)phenoxy!phenyl}pivalamide;or a salt, solvate,or physiologically functional derivative thereof.
 4. A pharmaceuticalformulation comprising a compound of formula (I) (as defined in claim1), or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof, and a pharmaceutically acceptable carrieror excipient.
 5. A process for preparing a compound of formula (I)according to claim 1, or a salt, solvate, or physiologically functionalderivative thereof; which comprises coupling a compound of formula (II)with a compound of formula (III); ##STR6## wherein, Y and Y" are groupscapable of reacting together to form the desired linkage Y (as definedfor formula (I));(WX)'-- is either the group W--X-- (wherein W and X areas defined for formula (I)), a protected form thereof, or a precursorfor the said group W--X--; --(EZ)' is either the group --E--Z (wherein Eand Z are as defined for formula (I)), a protected form thereof or aprecusor for the said group --E--Z; and rings A and B are optionallysubstituted as described for formula (I); to give either a compound offormula (I) or a compound of formula (IV): ##STR7## wherein Y is asdefined for formula (I), (WX)'-- and --(EZ)' are as defined for formulae(II) and (III) respectively (excluding combinations of (WX)'-- and--(EZ)' which give a compound of formula (I)), and rings A and B areoptionally substituted as described for formula (I); followed by,(i)When (WX)'-- in the compound of formula (II) is a precursor for thegroup W--X--, formation of the group W--X--; and/or (ii) When --(EZ)' inthe compound of formula (III) is a precursor for the group --E--Z;formation of the group --E--Z; and/or (iii) Removal of any protectinggroups; and/or (iv) Optional formation of a salt, solvate, orphysiologically functional derivative of the resulting compound offormula (I), as discussed below or conversion to a different compound offormula (I).
 6. A compound of formula (I) according to claim 1 wherein:Wis C₃₋₅ alkyl; X is --C(O)NH--; Y is ethenylene or --O--; E is --O--, ora bond; Z is a 5- or 6-membered saturated heterocylic ring and Z isoptionally substituted by one or more groups independently selected fromthe group consisting of halo, cyano, --CO₂ R⁶, --C(O)NR⁶ R⁷, --NR⁶ R⁷wherein R⁶ and R⁷ are independently hydrogen, --C₁₋₄ alkyl or C₋₄haloalkyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,hydroxy and C₂₋₈ polyether.
 7. A compound of formula (I) according toclaim 2 wherein:W is C₃₋₅ alkyl; X is --C(O)NH--; Y is ethenylene or--O--; E is --)--, or a bond; Z is a 5- or 6-membered saturatedheterocylic ring and Z is optionally substituted by one or more groupsindependently selected from the group consisting of halo, cyano, --CO₂R⁶, --C(O)NR⁶ R⁷, --NR⁶ R⁷ wherein R⁶ and R⁷ are independently hydrogen,C₁₋₄ alkyl or C₁₋₄ haloalkyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, hydroxy and C₂₋₈ polyether.
 8. A method for theprophylaxis or treatment of a clinical condition in a mammal, such as ahuman, for which an ACAT inhibitor is indicated, which comprises theadministration to the mammal of a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt, solvate,or physiologically functional derivative thereof ##STR8## wherein: W ishydrogen, or a C₁₋₁₂ hydrocarbyl group optionally substituted by one ormore groups independently selected from halo, C₁₋₄ alkyl, C₁₋₄ alkoxy,hydroxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and RC(O)-- (wherein R isselected from hydrogen, C₁₋₄ alkyl C₁₋₄ alkoxy, hydroxy, C₁₋₄ haloalkyl,and C₁₋₄ haloalkoxy);X is --NR¹ C(O)NR² --, --NR¹ C(O)--, --NR¹ C(O)O--,--C(O)NR² --, or --OC(O)NR² --(wherein R¹ and R² are independentlyselected from hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl); Y is a bond,C₂₋₄ alkynylene, C₂₋₄ alkenylene (cis or trans), C₁₋₄ alkylene,--(CH₂)_(n) --O--(CH₂)_(p) --, or --(CH₂)_(n) --S(O)_(q) --(CH₂)_(p) --,(wherein n and p are integers independently selected from 0, 1, 2, 3,and 4; providing that n+p is not greater than 4; and q is an integerselected from 0, 1, and 2), and Y is optionally substituted by one ormore groups independently selected from halo, C₁₋₄ alkyl, and C₁₋₄haloalkyl; E is a bond, C₁₋₄ alkylene, --(CH₂)_(r) O--(CH₂)_(s) --,--(CH₂)_(r) --S(O)_(t) --(CH₂)_(s) --, --(CH₂)_(r) --C(O)--(CH₂)_(s) --(wherein r and s are integers independently selected from 0, 1, 2, 3 and4; providing that r+s is not greater than 4; and t is an integerselected from 0, 1, and 2), --OC(O)--, --C(O)O--, --S(O)₂ N(R³)--,--(R³)NS(O)₂ --, --C(O)N(R³)--, --(R³)NC(O)N(R⁴)--, or --(R³)NC(O)--(wherein R³ and R⁴ are independently selected from hydrogen. C₁₋₄ alkyl,and C ₁₋₄ haloalkyl); Z is an aliphatic heterocyclic ring system orheteroaromatic, and Z is optionally substituted by one or more groupsindependently selected from halo, cyano, --CO₂ R⁶, --C(O)NR⁶ R⁷, --NR⁶R⁷ (wherein R⁶ and R⁷ are independently selected from hydrogen, C₁₋₄alkyl, and C₁₋₄ haloalkyl), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, hydroxy, and C₂₋₈ polyether; phenyl rings A and B areoptionally substituted by one or more groups independently selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₋₄ haloalkoxy, hydroxy,cyano, R⁸ R⁹ NC(O)--, R⁸ C(O)N(R⁹)--, R⁸ C(O)O--, and R⁸ C(O)-- (whereinR⁸ and R⁹ are independently selected from hydrogen, C₁₋₄ alkyl, and C₁₋₄haloalkyl);provided that if Y is methylene, ethylene, or n-propylene, or--CH═CH--(cis or trans), then group --E--Z is not C₁₋₆ alkyl optionallysubstituted by one or more independently selected polar groups.
 9. Amethod for the prophylaxis or treatment of a clinical condition in amammal, such as a human, for which an ACAT inhibitor is indicated, whichcomprises the administration to the mammal of a therapeuticallyeffective amount of a compound according to claim 1, or apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof.
 10. A method for the prophylaxis or treatment of aclinical condition in a mammal, such as a human, for which an ACATinhibitor is indicated, which comprises the administration to the mammalof a therapeutically effective amount of a compound according to claim2, or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof.
 11. A method for the prophylaxis ortreatment of a clinical condition in a mammal, such as a human, forwhich an ACAT inhibitor is indicated, which comprises the administrationto the mammal of a therapeutically effective amount of a compoundaccording to claim 3, or a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof.